Adult T-Cell Leukemia/Lymphoma

MONDO:0019471 Pathograph 21 Show in embeddings browser T-cell leukemia T-cell lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by persistent human T-lymphotropic virus type 1 (HTLV-1) infection. Only a minority of carriers develop ATL after a prolonged asymptomatic phase. Intermittent or early Tax signaling, persistent HBZ activity, and selected host somatic alterations cooperate in malignant CD4-positive T-cell expansion; Tax is therefore not modeled as the sole continuously expressed driver.

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7
Pathophys.
1
Histopath.
7
Phenotypes
21
Pathograph
2
Genes
4
Medical Actions
4
Subtypes
3
Datasets
10
References
1
Deep Research
🏷

Classifications

ICD-O Morphology
Lymphoma
Harrison's Part
ONCOLOGY HEMATOLOGY
NIH Highlighted Topic
NIH HT 42 rare cancers across cancer control continuum
◆

Subtypes

4
Acute ATLL
The acute subtype had a median survival of 6.2 months in the original Shimoyama classification cohort.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"MST was 6.2 months for acute type"
Shimoyama classification study confirms acute ATLL has median survival of 6.2 months, supporting the poor prognosis described.
Lymphoma Type ATLL
Lymphoma-type ATL is defined by histologically proven lymphadenopathy with no lymphocytosis and at most 1% abnormal circulating T lymphocytes.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and histologically-proven lymphadenopathy with or without extranodal lesions."
Shimoyama classification defines lymphoma type by lymphadenopathy without significant blood involvement.
Chronic ATLL
The chronic subtype had a median survival of 24.3 months in the original Shimoyama classification cohort.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"24.3 months for chronic type"
Shimoyama study shows chronic type has median survival of 24.3 months, supporting the better prognosis described.
Smoldering ATLL
Smoldering ATL usually has at least 5% abnormal peripheral-blood T lymphocytes with a normal absolute lymphocyte level and no hypercalcemia. With fewer than 5% abnormal T lymphocytes, a histologically proven skin or pulmonary lesion is required.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"Smouldering type, 5% or more abnormal lymphocytes of T-cell nature in PB, normal lymphocyte level (less than 4 x 10(9)/l), no hypercalcaemia (corrected calcium level less than 2.74 mmol/l), lactate dehydrogenase (LDH) value of up to 1.5 x the normal upper limit, no lymphadenopathy, no..."
Shimoyama classification defines the usual blood criteria and the histologically proven skin-or-lung exception when abnormal circulating T lymphocytes comprise less than 5%.
⚙

Pathophysiology

7
Persistent HTLV-1 Proviral Infection
Persistent HTLV-1 infection establishes clonally infected mature CD4-positive T cells. The provirus is integrated in ATL cells, while progression to malignancy occurs in only a minority of carriers.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
viral latency GO:0019042 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral latency (GO:0019042). GO:0019042 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Phase-Specific Tax Signaling The integrated HTLV-1 pX region encodes the Tax regulatory protein.
Persistent HBZ-Mediated Growth-Suppression Escape The proviral minus strand encodes HBZ, which remains expressed in ATL.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"HTLV-1 provirus is monoclonally integrated in ATL cells (Ohshima et al., 2017)."
The clinical review supports clonal HTLV-1 proviral integration in ATL cells.
Phase-Specific Tax Signaling
Tax is an HTLV-1 regulatory protein whose expression is phase-specific and often not maintained uniformly in established ATL. In primary acute-type ATL cells cultured ex vivo, Tax expression tracks induction of NF-kappaB species.
Downstream
Tax-Associated Canonical NF-kappaB Activation Tax induces nuclear NF-kappaB activity in acute-type primary ATL cells ex vivo.
Show evidence (1 reference)
PMID:10390192 SUPPORT In Vitro
"Expression of c-rel and KBF1 mRNAs in acute type cells appeared to be related to Tax mRNA expression."
Primary-cell culture data support phase-specific Tax signaling in acute ATL.
Persistent HBZ-Mediated Growth-Suppression Escape
HBZ is expressed from the HTLV-1 proviral minus strand and suppresses C/EBP-alpha-mediated growth restraint, supporting persistence and expansion of HTLV-1-infected cells even when Tax expression is not detectable.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Malignant CD4-Positive T-Cell Clonal Expansion HBZ-mediated suppression of C/EBP-alpha growth restraint supports proliferation of infected cells.
Show evidence (1 reference)
PMID:24359396 SUPPORT In Vitro
"Finally, HBZ selectively modulated the expression of C/EBPα target genes, leading to the impairment of C/EBPα-mediated cell growth suppression."
The experimental study directly supports the named HBZ growth-suppression mechanism.
Tax-Associated Canonical NF-kappaB Activation
Tax can induce canonical NF-kappaB activity, especially in acute-type primary ATL cells cultured ex vivo. Activity differs by clinical subtype, so this is not modeled as a uniformly constitutive Tax signal in every established tumor.
positive regulation of NF-kappaB transcription factor activity GO:0043123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves positive regulation of NF-kappaB transcription factor activity, annotated with positive regulation of canonical NF-kappaB signal transduction (GO:0043123), qualified as gain of function. GO:0043123 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Malignant CD4-Positive T-Cell Clonal Expansion NF-kappaB activity is associated with activation and proliferation of acute-type primary ATL cells.
Show evidence (1 reference)
PMID:10390192 SUPPORT In Vitro
"Marked NF-kappaB activity was detected using an electrophoretic mobility shift assay (EMSA) in the primary cells of patients with acute disease, but little activity was noted in the cells of chronic patients."
EMSA in primary ATL cells supports subtype-dependent NF-kappaB activation.
TP53-Mutant Senescence Escape
Somatic TP53 sequence or copy-number alterations mark an adverse ATL subset. Under AZT exposure, functional and patient evidence shows that wild-type p53 supports senescence and tumor-cell death, whereas mutated p53 is associated with treatment nonresponse and selection of an inactive-p53 clone at relapse. The modeled mechanism is explicitly bounded to this treatment context.
TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
cellular senescence GO:0090398 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Malignant CD4-Positive T-Cell Clonal Expansion Failure of AZT-induced p53-dependent senescence permits persistence and selection of a mutant malignant clone.
Show evidence (2 references)
PMID:16569765 SUPPORT In Vitro
"Here, we report that enduring AZT treatment of T-cell leukemia virus I-infected cells, in vitro and in vivo in ATL patients, results in inhibition of telomerase activity, progressive telomere shortening, and increased p14(ARF) expression. In turn, this elicits stabilization and reactivation of..."
The functional study defines the AZT-to-p53-dependent-senescence mechanism in infected cells and patients.
PMID:34405395 SUPPORT Human Clinical
"In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001)."
Human cohort data establish the adverse clinical association of TP53-altered ATL.
Somatic CCR4 Gain-of-Function Signaling
Recurrent truncating CCR4 variants impair receptor internalization and increase ligand-directed migration, PI3K-AKT signaling, and long-term growth in experimental ATL cells.
CCR4 hgnc:1605 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CCR4 (hgnc:1605). hgnc:1605 is a gene from the HUGO Gene Nomenclature Committee.
cell migration GO:0016477 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell migration (GO:0016477). GO:0016477 is a biological process from the Gene Ontology. ↑ INCREASED cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Malignant CD4-Positive T-Cell Clonal Expansion CCR4 gain of function provides migration and growth advantages to the ATL clone.
Show evidence (2 references)
PMID:25488980 SUPPORT Human Clinical
"CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330, or Y331 in the carboxy terminus."
Patient-tumor sequencing establishes recurrent truncating somatic CCR4 mutations.
PMID:25488980 SUPPORT In Vitro
"Functionally, the CCR4-Q330 nonsense isoform was gain-of-function because it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in part by impairing receptor internalization."
Functional assays establish gain of function and impaired internalization.
Malignant CD4-Positive T-Cell Clonal Expansion
Viral and host alterations converge on expansion of a mature activated CD4-positive malignant T-cell clone, producing leukemic, nodal, cutaneous, visceral, metabolic, and immunosuppressive manifestations that vary by clinical subtype.
CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Lymphocytosis Leukemic expansion produces peripheral-blood lymphocytosis in chronic ATL.
Lymphadenopathy Nodal malignant disease manifests as lymphadenopathy in lymphoma-type ATL.
Skin Lesions ATL can involve skin and produce variable eruptions.
Hepatomegaly Visceral ATL can involve the liver and present with enlargement.
Splenomegaly Visceral ATL can involve the spleen and present with enlargement.
Hypercalcemia Aggressive ATL, especially acute disease, is associated with hypercalcemia.
Recurrent Opportunistic Infections Indolent ATL can be accompanied by multiple infections, although the intervening immune mechanism is unresolved.
Show evidence (1 reference)
DOI:10.1182/blood-2011-03-345702 SUPPORT Other
"Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I."
The review supports the mature activated T-cell malignant endpoint.
✶

Histopathology

1
Flower-Cell Morphology of Malignant T Lymphocytes
Circulating malignant lymphoid cells can have markedly lobulated or indented nuclei, condensed chromatin, small or absent nucleoli, and agranular cytoplasm, producing the characteristic flower-cell appearance.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"exhibiting characteristic abnormal lymphoid cells with markedly lobulated, highly indented, or lobulated nuclei with condensed chromatin, small or absent nucleoli, and an agranular cytoplasm"
The diagnostic review defines the characteristic flower-cell morphology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adult T-Cell Leukemia/Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Blood 1
Lymphocytosis Increased total lymphocyte count HP:0100827 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total lymphocyte count (HP:0100827). HP:0100827 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"Chronic type, absolute lymphocytosis (4 x 10(9)/l or more) with T-lymphocytosis more than 3.5 x 10(9)/l"
The chronic-subtype criteria directly specify absolute and T-cell lymphocytosis.
Cardiovascular 2
Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and histologically-proven lymphadenopathy with or without extranodal lesions."
The ATLL lymphoma subtype is defined by histologically proven lymphadenopathy.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"The chronic type, lymphocytosis with a high percentage of leukemic cells, is occasionally associated with skin and lung involvement, lymphadenopathy, and hepatosplenomegaly"
The review explicitly includes hepatosplenomegaly in chronic ATL.
Digestive 1
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"The chronic type, lymphocytosis with a high percentage of leukemic cells, is occasionally associated with skin and lung involvement, lymphadenopathy, and hepatosplenomegaly"
The review explicitly includes hepatosplenomegaly in chronic ATL.
Integument 1
Skin Lesions Abnormal skin morphology HP:0011121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal skin morphology (HP:0011121). HP:0011121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:86875 SUPPORT Other
"Presentation is heterogeneous and is typically of aggressive leukemia or lymphoma, variable skin eruptions, and visceral organ involvement."
Orphanet directly lists variable skin eruptions as a typical presentation of adult T-cell leukemia/lymphoma.
Metabolism 1
Hypercalcemia FREQUENT HP:0003072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalcemia (HP:0003072). HP:0003072 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24714244 SUPPORT Human Clinical
"Hypercalcemia occurs in about 70% of patients with acute adult T cell leukemia."
The reported 70% prevalence in acute ATL falls within the 30–79% FREQUENT band.
Other 1
Recurrent Opportunistic Infections FREQUENT HP:0005390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent opportunistic infections (HP:0005390). HP:0005390 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Opportunistic infections frequent in HIV-infected individuals are also frequent in ATL patients."
The treatment review explicitly characterizes opportunistic infections as frequent in ATL.
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"These patients might experience multiple infections but can remain free of disease progression for many years"
The review supports multiple infections in indolent chronic or smoldering ATL.
PMID:8645790 SUPPORT Human Clinical
"Adult T-cell leukemia/lymphoma (ATLL) is caused by the human T-cell lymphotropic virus type I (HTLV-I). ATLL is classified into the smoldering, chronic, lymphoma, and acute subtypes. We describe a North American woman with chronic ATLL who presented with pneumonia caused by Pneumocystis carinii,..."
This case-review documents opportunistic and atypical infections in one chronic-ATL patient without establishing prevalence.
🧬

Genetic Associations

2
TP53 (Recurrent somatic alteration linked to adverse prognosis and treatment-context clonal selection)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (3 references)
PMID:34405395 SUPPORT Human Clinical
"Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations."
The cohort establishes recurrent tumor-associated TP53 alterations.
PMID:34405395 SUPPORT Human Clinical
"In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001)."
The cohort supports the adverse association of TP53-altered ATL.
PMID:16569765 SUPPORT Human Clinical
"While ATL patients carrying a wild-type p53 enter remission following treatment with AZT, those with a mutated p53 did not respond, and patients' disease relapse was associated with the selection of a tumor clone carrying mutated inactive p53."
Patient response and relapse data support mutated TP53 as a treatment-context selected somatic driver.
CCR4 (Recurrent somatic gain-of-function mutation in a subset of ATL)
Gene: CCR4 hgnc:1605 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CCR4 (hgnc:1605). hgnc:1605 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (3 references)
PMID:25488980 SUPPORT Human Clinical
"CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330, or Y331 in the carboxy terminus."
Patient-tumor sequencing establishes recurrent truncating CCR4 variants.
PMID:25488980 SUPPORT In Vitro
"Functionally, the CCR4-Q330 nonsense isoform was gain-of-function because it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in part by impairing receptor internalization."
Functional assays establish gain of function for a recurrent truncating isoform.
PMID:26437031 SUPPORT Human Clinical
"Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28)."
Integrated profiling of 426 ATL cases independently identifies CCR4 among recurrent activating alterations.
💊

Medical Actions

4
Chemotherapy
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Systemic chemotherapy produced a 49% overall response rate in the cited aggressive-ATL cohort; this entry does not extrapolate to every named regimen or duration of response.
Mechanism Target:
INHIBITS Malignant CD4-Positive T-Cell Clonal Expansion — Cytotoxic chemotherapy reduces clinically measurable malignant ATL burden.
Show evidence (1 reference)
PMID:22042945 SUPPORT Human Clinical
"The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α)."
Clinical response indirectly supports inhibition of malignant clonal burden.
Show evidence (1 reference)
PMID:22042945 SUPPORT Human Clinical
"The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α)."
Study shows chemotherapy alone achieves 49% response rate in aggressive ATLL, supporting modest efficacy.
Mogamulizumab
Category: Therapeutic Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: mogamulizumab NCIT:C62510 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses mogamulizumab (NCIT:C62510). NCIT:C62510 is a therapeutic agent from the NCI Thesaurus.
Mogamulizumab is a defucosylated anti-CCR4 monoclonal antibody approved in Japan for relapsed or refractory CCR4-positive ATL. The cited evidence does not establish CCR4 mutation as a response requirement.
Mechanism Target:
INHIBITS Malignant CD4-Positive T-Cell Clonal Expansion — CCR4 binding and enhanced ADCC target CCR4-positive ATL tumor cells.
Show evidence (1 reference)
PMID:30573506 SUPPORT Human Clinical
"Mogamulizumab is a first-in-class defucosylated humanized IgG1 kappa monoclonal antibody that selectively binds to CCR4 and has enhanced antibody-dependent cellular cytotoxicity (ADCC) activity."
The trial report supports CCR4-positive tumor-cell targeting through binding and ADCC.
Show evidence (2 references)
PMID:30573506 SUPPORT Human Clinical
"mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile."
The international phase II trial reported an 11% composite overall response rate with a tolerable safety profile.
PMID:30573506 SUPPORT Human Clinical
"Mogamulizumab is approved in Japan for the treatment of relapsed/refractory CCR4+ ATL on the basis of a phase II trial showing a 50% overall response rate (ORR) in a relapsed population."
The trial report directly supports the Japan-specific approval statement.
Allogeneic Stem Cell Transplantation
Category: Therapeutic Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Allogeneic hematopoietic stem-cell transplantation can provide selected transplant-eligible patients with aggressive ATL a chance of long-term remission through a graft-versus-ATL effect.
Mechanism Target:
INHIBITS Malignant CD4-Positive T-Cell Clonal Expansion — The graft-versus-ATL effect can suppress the malignant ATL clone.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Thus, allo-HSCT can provide a chance of long-term remission through a graft- versus-ATL (GvATL) effect"
The graft-versus-ATL effect supports clonal inhibition without resolving every immune effector step.
Show evidence (2 references)
PMID:30573506 SUPPORT Human Clinical
"Allogeneic stem cell transplantation (allo-SCT) can significantly prolong survival, but there are few appropriate candidates"
The study states that allo-SCT can prolong survival while noting that few patients are appropriate candidates.
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Thus, allo-HSCT can provide a chance of long-term remission through a graft- versus-ATL (GvATL) effect"
The treatment review supports the bounded long-term-remission and GvATL claims.
Interferon-alpha and Zidovudine
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: recombinant interferon alfa NCIT:C225 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant interferon alfa (NCIT:C225). NCIT:C225 is a therapeutic agent from the NCI Thesaurus. zidovudine CHEBI:10110 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses zidovudine (CHEBI:10110). CHEBI:10110 is a therapeutic agent from Chemical Entities of Biological Interest.
Zidovudine plus interferon-alpha was associated with prolonged survival in acute and lymphoma ATL in the cited retrospective cohort. No molecular treatment-target edge is asserted from survival evidence alone.
Show evidence (1 reference)
PMID:22042945 SUPPORT Human Clinical
"Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL"
UK study demonstrated ZDV/IFN-α significantly prolonged survival in both acute and lymphoma ATLL subtypes.
🔬

Biochemical Markers

3
HTLV-1 Antibodies (Positive)
Context: HTLV-1 seropositivity supports ATL only together with histologically or cytologically proven peripheral T-cell malignancy.
Pathograph Readouts
Readout Of Persistent HTLV-1 Proviral Infection Present Absent Diagnostic
Anti-HTLV-1 seropositivity documents infection but is not sufficient alone to diagnose ATL.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Clinically, the diagnosis of ATL is made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1 carriers have been reported"
The review requires seropositivity to be interpreted with malignant-cell confirmation and notes a specificity limitation in carriers.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Clinically, the diagnosis of ATL is made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1 carriers have been reported"
The diagnostic review supports anti-HTLV-1 seropositivity as one component of diagnosis rather than a stand-alone discriminator.
Clonal HTLV-1 Proviral Integration (Detected)
Context: Demonstration of clonal proviral integration in tumor cells provides biologic confirmation of ATL; detection should be interpreted in the full clinicopathologic context.
Pathograph Readouts
Readout Of Persistent HTLV-1 Proviral Infection Present Absent Diagnostic
Clonal integration in tumor cells demonstrates the persistent proviral state underlying ATL.
Show evidence (1 reference)
PMID:15129647 SUPPORT Other
"The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL."
The review identifies clonal proviral integration in tumor cells as biologic confirmation.
Show evidence (1 reference)
PMID:15129647 SUPPORT Other
"The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL."
The review directly supports this biologic diagnostic readout.
Soluble IL-2 Receptor (sIL-2R) (Elevated)
Context: In a prospective cohort receiving mogamulizumab-containing treatment, higher baseline sIL-2R was an independent unfavorable prognostic factor for overall survival; this entry does not assert that sIL-2R directly measures tumor burden.
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2020003053 SUPPORT Human Clinical
"Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD2−CD19+ B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS."
The prospective treated cohort supports higher sIL-2R as an adverse prognostic biomarker.
🔬

Diagnosis

4
HTLV-1 Serology with Malignant T-Cell Confirmation
Anti-HTLV-1 seropositivity documents infection but supports ATL only in a compatible malignant mature T-cell clinicopathologic context.
serology testing NCIT:C25294 NCI Thesaurus (NCIT)
Results: Anti-HTLV-1 antibodies are detected.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Clinically, the diagnosis of ATL is made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1 carriers have been reported"
The review requires infection evidence to be combined with malignant-cell confirmation and notes the carrier-state specificity limitation.
Histologic or Cytologic Confirmation of Peripheral T-Cell Malignancy
Histologic or cytologic examination must establish a compatible peripheral T-cell malignancy in the HTLV-1-seropositive patient.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Compatible malignant peripheral T cells are demonstrated histologically or cytologically.
Show evidence (1 reference)
DOI:10.3389/fmicb.2020.01207 SUPPORT Other
"Clinically, the diagnosis of ATL is made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1 carriers have been reported"
The review explicitly requires pathologic malignant-cell confirmation alongside HTLV-1 seropositivity.
Clonal HTLV-1 Proviral Integration Analysis
Southern blot analysis can demonstrate clonal HTLV-1 proviral integration in tumor cells as biologic confirmation.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: A clonally integrated HTLV-1 provirus in tumor cells biologically supports ATL.
Show evidence (1 reference)
PMID:15129647 SUPPORT Other
"The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL."
The review defines this molecular finding as biologic confirmation of ATL.
Shimoyama Clinical Subtype Classification
Clinical and laboratory findings are used to assign acute, lymphoma, chronic, or smoldering ATL; the original cohort documented distinct clinical features and markedly different survival across these subtypes.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: The presentation is assigned to one of four clinicopathologic subtypes.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"The following diagnostic criteria are proposed to classify four clinical subtypes of HTLV-1 associated adult T-cell leukaemia-lymphoma (ATL)"
The 818-patient classification study establishes the four-subtype framework.
📈

Progression

2
Persistent asymptomatic HTLV-1 carrier state
Most HTLV-1 carriers remain asymptomatic; a minority lose immune control and develop ATL after a prolonged carrier phase.
Show evidence (1 reference)
DOI:10.3390/biom13101543 SUPPORT Other
"HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5–10% of carriers lose this balance and develop ATL."
The review supports the prolonged carrier phase and minority progression to ATL.
Subtype-dependent clinical course
Clinical course differs substantially across acute, lymphoma, chronic, and smoldering ATL, with the original classification cohort showing shortest survival in acute disease and longer survival in chronic and smoldering disease.
Show evidence (1 reference)
PMID:1751370 SUPPORT Human Clinical
"MST was 6.2 months for acute type, 10.2 months for lymphoma type, 24.3 months for chronic type, and not yet reached for smouldering type."
The 818-patient classification cohort quantifies the subtype-dependent course.
🦠

Infectious Agent

1
Human T-Lymphotropic Virus Type 1 (HTLV-1)
HTLV-1 is an oncoretrovirus transmitted vertically, horizontally, and through blood transfusion. It establishes persistent proviral infection of T cells; phase-specific Tax and persistent HBZ activity are represented separately in the causal graph.
Human T-cell leukemia virus type I NCBITaxon:11908 NCBI Taxonomy (NCBITaxon)
Show evidence (2 references)
PMID:41553980 SUPPORT Human Clinical
"HTLV-1 is a retrovirus associated with adult T cell leukemia/lymphoma (ATL) and inflammatory diseases, including HTLV-1-associated myelopathy (HAM) and HTLV-1-associated bronchopneumonopathy (HAB)."
This abstract explicitly links HTLV-1 to adult T-cell leukemia/lymphoma, supporting the infectious etiology.
PMID:15129647 SUPPORT Other
"This oncoretrovirus can be transmitted through 3 ways: horizontally, vertically (mother to child) and via blood transfusion."
The review supports the stated transmission routes.
📊

Related Datasets

3
Whole Genome sequencing of adult T-cell leukemia/lymphoma ega:EGAS00001001210
Whole Genome sequencing of a single adult T-cell leukemia/lymphoma case
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Integrated molecular analysis of adult T-cell leukemia/lymphoma ega:EGAS00001001296
This study is an integrated molecular study of adult T-cell leukemia/lymphoma which includes whole-exome (n = 81), whole-genome (n = 48), and transcriptome sequencing data (n = 57) as well as methylation (n = 109) and SNP array data (n = 426)
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
RNA-sequencing of adult T-cell leukemia/lymphoma samples ega:EGAS00001003575
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. In this study, we performed RNA-sequencing (RNA-seq) analysis for ATL samples including 9 primary tumors and 1 ATL cell line to clarify gene expression profiles in this disease.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
{ }

Source YAML

click to show 
name: Adult T-Cell Leukemia/Lymphoma
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm
  caused by persistent human T-lymphotropic virus type 1 (HTLV-1) infection.
  Only a minority of carriers develop ATL after a prolonged asymptomatic phase.
  Intermittent or early Tax signaling, persistent HBZ activity, and selected host
  somatic alterations cooperate in malignant CD4-positive T-cell expansion; Tax
  is therefore not modeled as the sole continuously expressed driver.
categories:
- Hematologic Malignancy
- T-Cell Lymphoma
- Virus-Associated Cancer
parents:
- T-cell leukemia
- T-cell lymphoma
has_subtypes:
- name: Acute ATLL
  description: >-
    The acute subtype had a median survival of 6.2 months in the original
    Shimoyama classification cohort.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MST was 6.2 months for acute type
    explanation: >-
      Shimoyama classification study confirms acute ATLL has median survival
      of 6.2 months, supporting the poor prognosis described.
- name: Lymphoma Type ATLL
  description: >-
    Lymphoma-type ATL is defined by histologically proven lymphadenopathy with
    no lymphocytosis and at most 1% abnormal circulating T lymphocytes.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and
      histologically-proven lymphadenopathy with or without extranodal lesions.
    explanation: >-
      Shimoyama classification defines lymphoma type by lymphadenopathy without
      significant blood involvement.
- name: Chronic ATLL
  description: >-
    The chronic subtype had a median survival of 24.3 months in the original
    Shimoyama classification cohort.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      24.3 months for chronic type
    explanation: >-
      Shimoyama study shows chronic type has median survival of 24.3 months,
      supporting the better prognosis described.
- name: Smoldering ATLL
  description: >-
    Smoldering ATL usually has at least 5% abnormal peripheral-blood T
    lymphocytes with a normal absolute lymphocyte level and no hypercalcemia.
    With fewer than 5% abnormal T lymphocytes, a histologically proven skin or
    pulmonary lesion is required.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Smouldering type, 5% or more abnormal lymphocytes of T-cell nature in PB,
      normal lymphocyte level (less than 4 x 10(9)/l), no hypercalcaemia
      (corrected calcium level less than 2.74 mmol/l), lactate dehydrogenase
      (LDH) value of up to 1.5 x the normal upper limit, no lymphadenopathy, no
      involvement of liver, spleen, central nervous system (CNS), bone and
      gastrointestinal tract, and neither ascites nor pleural effusion. Skin
      and pulmonary lesion(s) may be present. In case of less than 5% abnormal
      T-lymphocytes in PB, at least one of histologically-proven skin and
      pulmonary lesions should be present.
    explanation: >-
      Shimoyama classification defines the usual blood criteria and the
      histologically proven skin-or-lung exception when abnormal circulating T
      lymphocytes comprise less than 5%.
progression:
- phase: Persistent asymptomatic HTLV-1 carrier state
  notes: >-
    Most HTLV-1 carriers remain asymptomatic; a minority lose immune control and
    develop ATL after a prolonged carrier phase.
  evidence:
  - reference: DOI:10.3390/biom13101543
    reference_title: "Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HTLV-1 carriers have a lifelong asymptomatic balance between infected
      cells and host antiviral immunity; however, 5–10% of carriers lose this
      balance and develop ATL.
    explanation: The review supports the prolonged carrier phase and minority progression to ATL.
- phase: Subtype-dependent clinical course
  notes: >-
    Clinical course differs substantially across acute, lymphoma, chronic, and
    smoldering ATL, with the original classification cohort showing shortest
    survival in acute disease and longer survival in chronic and smoldering disease.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MST was 6.2 months for acute type, 10.2 months for lymphoma type, 24.3
      months for chronic type, and not yet reached for smouldering type.
    explanation: The 818-patient classification cohort quantifies the subtype-dependent course.
infectious_agent:
- name: Human T-Lymphotropic Virus Type 1 (HTLV-1)
  infectious_agent_term:
    preferred_term: Human T-cell leukemia virus type I
    term:
      id: NCBITaxon:11908
      label: Human T-cell leukemia virus type I
  description: >-
    HTLV-1 is an oncoretrovirus transmitted vertically, horizontally, and through
    blood transfusion. It establishes persistent proviral infection of T cells;
    phase-specific Tax and persistent HBZ activity are represented separately in
    the causal graph.
  evidence:
  - reference: PMID:41553980
    reference_title: "CXCR3/CXCL10 Axis-Mediated T Cell Infiltration in the Lungs of Patients With HTLV-1-Associated Diseases: Implications for Subclinical Pulmonary Involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HTLV-1 is a retrovirus associated with adult T cell leukemia/lymphoma (ATL) and inflammatory diseases, including HTLV-1-associated myelopathy (HAM) and HTLV-1-associated bronchopneumonopathy (HAB)."
    explanation: This abstract explicitly links HTLV-1 to adult T-cell leukemia/lymphoma, supporting the infectious etiology.
  - reference: PMID:15129647
    reference_title: "HTLV-1 and associated adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This oncoretrovirus can be transmitted through 3 ways: horizontally,
      vertically (mother to child) and via blood transfusion.
    explanation: The review supports the stated transmission routes.
pathophysiology:
- name: Persistent HTLV-1 Proviral Infection
  conforms_to: "viral_oncogenesis#Persistent Oncogenic Virus Infection"
  description: >-
    Persistent HTLV-1 infection establishes clonally infected mature CD4-positive
    T cells. The provirus is integrated in ATL cells, while progression to
    malignancy occurs in only a minority of carriers.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: viral latency
    term:
      id: GO:0019042
      label: viral latency
    modifier: INCREASED
  downstream:
  - target: Phase-Specific Tax Signaling
    description: The integrated HTLV-1 pX region encodes the Tax regulatory protein.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15129647
      reference_title: "HTLV-1 and associated adult T-cell leukemia/lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus."
      explanation: This review identifies Tax as a protein encoded by integrated HTLV-1.
  - target: Persistent HBZ-Mediated Growth-Suppression Escape
    description: The proviral minus strand encodes HBZ, which remains expressed in ATL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24359396
      reference_title: "HTLV-1 bZIP factor supports proliferation of adult T cell leukemia cells through suppression of C/EBPα signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The HTLV-1 bZIP factor (HBZ), which is encoded by minus strand of
        provirus, is expressed in all ATL cases and supports the proliferation
        of ATL cells.
      explanation: The study identifies provirus-encoded HBZ and its persistent expression in ATL.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HTLV-1 provirus is monoclonally integrated in ATL cells (Ohshima et al., 2017)."
    explanation: The clinical review supports clonal HTLV-1 proviral integration in ATL cells.
- name: Phase-Specific Tax Signaling
  conforms_to: "viral_oncogenesis#Viral Oncoprotein Expression and Genome Integration"
  description: >-
    Tax is an HTLV-1 regulatory protein whose expression is phase-specific and
    often not maintained uniformly in established ATL. In primary acute-type ATL
    cells cultured ex vivo, Tax expression tracks induction of NF-kappaB species.
  downstream:
  - target: Tax-Associated Canonical NF-kappaB Activation
    description: Tax induces nuclear NF-kappaB activity in acute-type primary ATL cells ex vivo.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10390192
      reference_title: "NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These results suggest that Tax is capable of inducing nuclear expression
        of all four NF-kappaB species in primary ATL cells of acute type patients,
        with marked effects on p55, p75, and p85.
      explanation: Cultured primary ATL cells support Tax-dependent NF-kappaB induction in acute disease.
  evidence:
  - reference: PMID:10390192
    reference_title: "NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of c-rel and KBF1 mRNAs in acute type cells appeared to be
      related to Tax mRNA expression.
    explanation: Primary-cell culture data support phase-specific Tax signaling in acute ATL.
- name: Persistent HBZ-Mediated Growth-Suppression Escape
  conforms_to: "viral_oncogenesis#Viral Oncoprotein Expression and Genome Integration"
  description: >-
    HBZ is expressed from the HTLV-1 proviral minus strand and suppresses
    C/EBP-alpha-mediated growth restraint, supporting persistence and expansion
    of HTLV-1-infected cells even when Tax expression is not detectable.
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    description: HBZ-mediated suppression of C/EBP-alpha growth restraint supports proliferation of infected cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - suppression of C/EBP-alpha-mediated cell-growth restraint
    evidence:
    - reference: PMID:24359396
      reference_title: "HTLV-1 bZIP factor supports proliferation of adult T cell leukemia cells through suppression of C/EBPα signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        HBZ, by suppressing C/EBPα signaling, supports the proliferation of
        HTLV-1 infected cells, which is thought to be critical for oncogenesis.
      explanation: Cell-based experiments identify C/EBP-alpha suppression as an intermediate growth mechanism.
  evidence:
  - reference: PMID:24359396
    reference_title: "HTLV-1 bZIP factor supports proliferation of adult T cell leukemia cells through suppression of C/EBPα signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, HBZ selectively modulated the expression of C/EBPα target genes,
      leading to the impairment of C/EBPα-mediated cell growth suppression.
    explanation: The experimental study directly supports the named HBZ growth-suppression mechanism.
- name: Tax-Associated Canonical NF-kappaB Activation
  conforms_to: "viral_oncogenesis#Host Tumor Suppressor Inactivation and Signaling Hijack"
  description: >-
    Tax can induce canonical NF-kappaB activity, especially in acute-type primary
    ATL cells cultured ex vivo. Activity differs by clinical subtype, so this is
    not modeled as a uniformly constitutive Tax signal in every established tumor.
  biological_processes:
  - preferred_term: positive regulation of NF-kappaB transcription factor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
  downstream:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    description: NF-kappaB activity is associated with activation and proliferation of acute-type primary ATL cells.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10390192
      reference_title: "NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Tax induction of NF-kappaB is presumed to be involved in proliferation
        and activation of primary leukemia cells in vivo.
      explanation: The source proposes this route, but the proliferative intermediates are not directly established.
  evidence:
  - reference: PMID:10390192
    reference_title: "NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Marked NF-kappaB activity was detected using an electrophoretic mobility
      shift assay (EMSA) in the primary cells of patients with acute disease, but
      little activity was noted in the cells of chronic patients.
    explanation: EMSA in primary ATL cells supports subtype-dependent NF-kappaB activation.
- name: TP53-Mutant Senescence Escape
  conforms_to: "viral_oncogenesis#Host Tumor Suppressor Inactivation and Signaling Hijack"
  description: >-
    Somatic TP53 sequence or copy-number alterations mark an adverse ATL subset.
    Under AZT exposure, functional and patient evidence shows that wild-type p53
    supports senescence and tumor-cell death, whereas mutated p53 is associated
    with treatment nonresponse and selection of an inactive-p53 clone at relapse.
    The modeled mechanism is explicitly bounded to this treatment context.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  biological_processes:
  - preferred_term: cellular senescence
    modifier: DECREASED
    term:
      id: GO:0090398
      label: cellular senescence
  downstream:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    description: Failure of AZT-induced p53-dependent senescence permits persistence and selection of a mutant malignant clone.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of telomerase-inhibition-induced p53 reactivation, senescence, and tumor-cell death
    evidence:
    - reference: PMID:16569765
      reference_title: "Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While ATL patients carrying a wild-type p53 enter remission following
        treatment with AZT, those with a mutated p53 did not respond, and
        patients' disease relapse was associated with the selection of a tumor
        clone carrying mutated inactive p53.
      explanation: Patient response and relapse data support treatment-context persistence and selection of mutated-p53 ATL clones.
  evidence:
  - reference: PMID:16569765
    reference_title: "Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we report that enduring AZT treatment of T-cell leukemia virus
      I-infected cells, in vitro and in vivo in ATL patients, results in
      inhibition of telomerase activity, progressive telomere shortening, and
      increased p14(ARF) expression. In turn, this elicits stabilization and
      reactivation of the tumor suppressor p53-dependent transcription,
      increased expression of the cyclin-dependent kinase inhibitor p21(Waf1),
      and accumulation of p27(kip1), thereby inducing cellular senescence and
      tumor cell death.
    explanation: The functional study defines the AZT-to-p53-dependent-senescence mechanism in infected cells and patients.
  - reference: PMID:34405395
    reference_title: "Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the entire cohort, median survival of patients with and without TP53
      mutations was 1·0 and 6·7 years respectively (P < 0·001).
    explanation: Human cohort data establish the adverse clinical association of TP53-altered ATL.
- name: Somatic CCR4 Gain-of-Function Signaling
  description: >-
    Recurrent truncating CCR4 variants impair receptor internalization and
    increase ligand-directed migration, PI3K-AKT signaling, and long-term growth
    in experimental ATL cells.
  genes:
  - preferred_term: CCR4
    term:
      id: hgnc:1605
      label: CCR4
  biological_processes:
  - preferred_term: cell migration
    term:
      id: GO:0016477
      label: cell migration
    modifier: INCREASED
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  downstream:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    description: CCR4 gain of function provides migration and growth advantages to the ATL clone.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired CCR4 internalization and enhanced CCL22-triggered PI3K-AKT signaling
    evidence:
    - reference: PMID:25488980
      reference_title: "Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This mutant enhanced PI(3) kinase/AKT activation after receptor engagement
        by CCL22 in ATLL cells and conferred a growth advantage in long-term in
        vitro cultures.
      explanation: Functional experiments define the signaling and growth intermediates.
  evidence:
  - reference: PMID:25488980
    reference_title: "Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted
      exclusively of nonsense or frameshift mutations that truncated the coding
      region at C329, Q330, or Y331 in the carboxy terminus.
    explanation: Patient-tumor sequencing establishes recurrent truncating somatic CCR4 mutations.
  - reference: PMID:25488980
    reference_title: "Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functionally, the CCR4-Q330 nonsense isoform was gain-of-function because
      it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in
      part by impairing receptor internalization.
    explanation: Functional assays establish gain of function and impaired internalization.
- name: Malignant CD4-Positive T-Cell Clonal Expansion
  conforms_to: "viral_oncogenesis#Malignant Transformation"
  description: >-
    Viral and host alterations converge on expansion of a mature activated
    CD4-positive malignant T-cell clone, producing leukemic, nodal, cutaneous,
    visceral, metabolic, and immunosuppressive manifestations that vary by
    clinical subtype.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Lymphocytosis
    description: Leukemic expansion produces peripheral-blood lymphocytosis in chronic ATL.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:1751370
      reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Chronic type, absolute lymphocytosis (4 x 10(9)/l or more) with T-lymphocytosis
        more than 3.5 x 10(9)/l
      explanation: The subtype criteria directly connect the leukemic presentation to lymphocytosis.
  - target: Lymphadenopathy
    description: Nodal malignant disease manifests as lymphadenopathy in lymphoma-type ATL.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1751370
      reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and
        histologically-proven lymphadenopathy with or without extranodal lesions.
      explanation: The cohort establishes nodal disease occurrence but not every intervening tissue mechanism.
  - target: Skin Lesions
    description: ATL can involve skin and produce variable eruptions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:86875
      reference_title: Adult T-cell leukemia/lymphoma
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Presentation is heterogeneous and is typically of aggressive leukemia or
        lymphoma, variable skin eruptions, and visceral organ involvement.
      explanation: Orphanet supports occurrence while the tissue route remains unresolved.
  - target: Hepatomegaly
    description: Visceral ATL can involve the liver and present with enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1751370
      reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lymphadenopathy and involvement of liver, spleen, skin, and lung may be
        present
      explanation: The criteria support liver involvement but only indirectly support enlargement.
  - target: Splenomegaly
    description: Visceral ATL can involve the spleen and present with enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1751370
      reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lymphadenopathy and involvement of liver, spleen, skin, and lung may be
        present
      explanation: The criteria support spleen involvement but only indirectly support enlargement.
  - target: Hypercalcemia
    description: Aggressive ATL, especially acute disease, is associated with hypercalcemia.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:24714244
      reference_title: "Hypercalcemic crisis due to adult T cell leukemia: a rare cause of paralytic ileus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypercalcemia occurs in about 70% of patients with acute adult T cell leukemia."
      explanation: The clinical source supports the acute-subtype association; the causal route is not resolved.
  - target: Recurrent Opportunistic Infections
    description: Indolent ATL can be accompanied by multiple infections, although the intervening immune mechanism is unresolved.
    causal_link_type: UNKNOWN
    evidence:
    - reference: DOI:10.3389/fmicb.2020.01207
      reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These patients might experience multiple infections but can remain free
        of disease progression for many years
      explanation: The review supports multiple infections in indolent ATL but does not resolve the causal route from the malignant clone.
  evidence:
  - reference: DOI:10.1182/blood-2011-03-345702
    reference_title: "How I treat adult T-cell leukemia/lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature
      activated T cells caused by human T-cell lymphotropic virus type I.
    explanation: The review supports the mature activated T-cell malignant endpoint.
histopathology:
- name: Flower-Cell Morphology of Malignant T Lymphocytes
  finding_term:
    preferred_term: Flower-cell morphology of malignant T lymphocytes
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  diagnostic: false
  description: >-
    Circulating malignant lymphoid cells can have markedly lobulated or indented
    nuclei, condensed chromatin, small or absent nucleoli, and agranular
    cytoplasm, producing the characteristic flower-cell appearance.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      exhibiting characteristic abnormal lymphoid cells with markedly lobulated,
      highly indented, or lobulated nuclei with condensed chromatin, small or
      absent nucleoli, and an agranular cytoplasm
    explanation: The diagnostic review defines the characteristic flower-cell morphology.

phenotypes:
- category: Hematologic
  name: Lymphocytosis
  subtype: Chronic ATLL
  description: >-
    The chronic subtype is defined in part by absolute lymphocytosis with
    T-lymphocytosis; flower-cell morphology is represented separately under
    histopathology.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic type, absolute lymphocytosis (4 x 10(9)/l or more) with T-lymphocytosis
      more than 3.5 x 10(9)/l
    explanation: The chronic-subtype criteria directly specify absolute and T-cell lymphocytosis.
  phenotype_term:
    preferred_term: Increased total lymphocyte count
    term:
      id: HP:0100827
      label: Increased total lymphocyte count
- category: Lymphatic
  name: Lymphadenopathy
  subtype: Lymphoma Type ATLL
  description: >-
    Histologically proven lymphadenopathy, with or without extranodal lesions,
    defines lymphoma-type ATL when substantial blood lymphocytosis is absent.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and
      histologically-proven lymphadenopathy with or without extranodal lesions.
    explanation: The ATLL lymphoma subtype is defined by histologically proven lymphadenopathy.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
- category: Metabolic
  name: Hypercalcemia
  frequency: FREQUENT
  subtype: Acute ATLL
  description: >-
    Hypercalcemia occurs in about 70% of acute ATL cases. It is subtype-scoped
    here and is not treated as a disease-wide diagnostic requirement.
  evidence:
  - reference: PMID:24714244
    reference_title: "Hypercalcemic crisis due to adult T cell leukemia: a rare cause of paralytic ileus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypercalcemia occurs in about 70% of patients with acute adult T cell leukemia."
    explanation: The reported 70% prevalence in acute ATL falls within the 30–79% FREQUENT band.
  phenotype_term:
    preferred_term: Hypercalcemia
    term:
      id: HP:0003072
      label: Hypercalcemia
- category: Dermatologic
  name: Skin Lesions
  description: >-
    ATL has heterogeneous presentation and can include variable skin eruptions.
  evidence:
  - reference: ORPHA:86875
    reference_title: Adult T-cell leukemia/lymphoma
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Presentation is heterogeneous and is typically of aggressive leukemia or
      lymphoma, variable skin eruptions, and visceral organ involvement.
    explanation: Orphanet directly lists variable skin eruptions as a typical presentation of adult T-cell leukemia/lymphoma.
  phenotype_term:
    preferred_term: Abnormal skin morphology
    term:
      id: HP:0011121
      label: Abnormal skin morphology
- category: Abdominal
  name: Hepatomegaly
  subtype: Chronic ATLL
  description: >-
    Hepatosplenomegaly may accompany chronic ATL; no disease-wide frequency is
    inferred from the subtype description.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The chronic type, lymphocytosis with a high percentage of leukemic cells,
      is occasionally associated with skin and lung involvement,
      lymphadenopathy, and hepatosplenomegaly
    explanation: The review explicitly includes hepatosplenomegaly in chronic ATL.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- category: Abdominal
  name: Splenomegaly
  subtype: Chronic ATLL
  description: >-
    Hepatosplenomegaly may accompany chronic ATL; no disease-wide frequency is
    inferred from the subtype description.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The chronic type, lymphocytosis with a high percentage of leukemic cells,
      is occasionally associated with skin and lung involvement,
      lymphadenopathy, and hepatosplenomegaly
    explanation: The review explicitly includes hepatosplenomegaly in chronic ATL.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
- category: Infectious
  name: Recurrent Opportunistic Infections
  frequency: FREQUENT
  description: >-
    Opportunistic infections are frequent in ATL, and patients with indolent
    disease may experience multiple infections. A chronic-ATL case documents
    simultaneous Pneumocystis, cryptococcal, mycoplasmal, and mycobacterial
    pulmonary infections.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Opportunistic infections frequent in HIV-infected individuals are also
      frequent in ATL patients.
    explanation: The treatment review explicitly characterizes opportunistic infections as frequent in ATL.
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These patients might experience multiple infections but can remain free
      of disease progression for many years
    explanation: The review supports multiple infections in indolent chronic or smoldering ATL.
  - reference: PMID:8645790
    reference_title: "Infections in patients with chronic adult T-cell leukemia/lymphoma: case report and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adult T-cell leukemia/lymphoma (ATLL) is caused by the human T-cell
      lymphotropic virus type I (HTLV-I). ATLL is classified into the smoldering,
      chronic, lymphoma, and acute subtypes. We describe a North American woman
      with chronic ATLL who presented with pneumonia caused by Pneumocystis
      carinii, Cryptococcus neoformans, Mycoplasma pneumoniae, and Mycobacterium
      avium complex.
    explanation: This case-review documents opportunistic and atypical infections in one chronic-ATL patient without establishing prevalence.
  phenotype_term:
    preferred_term: Recurrent opportunistic infections
    term:
      id: HP:0005390
      label: Recurrent opportunistic infections
biochemical:
- name: HTLV-1 Antibodies
  presence: Positive
  context: >-
    HTLV-1 seropositivity supports ATL only together with histologically or
    cytologically proven peripheral T-cell malignancy.
  readouts:
  - target: Persistent HTLV-1 Proviral Infection
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: Anti-HTLV-1 seropositivity documents infection but is not sufficient alone to diagnose ATL.
    evidence:
    - reference: DOI:10.3389/fmicb.2020.01207
      reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinically, the diagnosis of ATL is made based on seropositivity for
        HTLV-1 and histologically and/or cytologically proven peripheral T cell
        lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1
        carriers have been reported
      explanation: The review requires seropositivity to be interpreted with malignant-cell confirmation and notes a specificity limitation in carriers.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, the diagnosis of ATL is made based on seropositivity for
      HTLV-1 and histologically and/or cytologically proven peripheral T cell
      lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1
      carriers have been reported
    explanation: The diagnostic review supports anti-HTLV-1 seropositivity as one component of diagnosis rather than a stand-alone discriminator.
- name: Clonal HTLV-1 Proviral Integration
  presence: Detected
  context: >-
    Demonstration of clonal proviral integration in tumor cells provides
    biologic confirmation of ATL; detection should be interpreted in the full
    clinicopathologic context.
  readouts:
  - target: Persistent HTLV-1 Proviral Infection
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: Clonal integration in tumor cells demonstrates the persistent proviral state underlying ATL.
    evidence:
    - reference: PMID:15129647
      reference_title: "HTLV-1 and associated adult T-cell leukemia/lymphoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The demonstration by Southern blot analysis of the clonal integration
        of an HTLV-1 provirus in the tumoral cells represents the gold-standard
        to define biologically ATLL.
      explanation: The review identifies clonal proviral integration in tumor cells as biologic confirmation.
  evidence:
  - reference: PMID:15129647
    reference_title: "HTLV-1 and associated adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The demonstration by Southern blot analysis of the clonal integration of
      an HTLV-1 provirus in the tumoral cells represents the gold-standard to
      define biologically ATLL.
    explanation: The review directly supports this biologic diagnostic readout.
- name: Soluble IL-2 Receptor (sIL-2R)
  presence: Elevated
  context: >-
    In a prospective cohort receiving mogamulizumab-containing treatment,
    higher baseline sIL-2R was an independent unfavorable prognostic factor for
    overall survival; this entry does not assert that sIL-2R directly measures
    tumor burden.
  evidence:
  - reference: DOI:10.1182/bloodadvances.2020003053
    reference_title: "Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multivariate analysis identified the clinical subtype (acute or lymphoma
      type), a higher sIL-2R level, and a lower percentage of CD2−CD19+ B cells
      in peripheral blood mononuclear cells as significant independent
      unfavorable prognostic factors for OS.
    explanation: The prospective treated cohort supports higher sIL-2R as an adverse prognostic biomarker.
genetic:
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Recurrent somatic alteration linked to adverse prognosis and treatment-context clonal selection
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    TP53 sequence variants or copy-number alterations occurred in 67 of 177
    patients and were associated with substantially shorter median survival. A
    functional study linked mutated p53 to AZT nonresponse and selection of an
    inactive-p53 clone at relapse.
  evidence:
  - reference: PMID:34405395
    reference_title: "Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs,
      and were categorized as having TP53 mutations.
    explanation: The cohort establishes recurrent tumor-associated TP53 alterations.
  - reference: PMID:34405395
    reference_title: "Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the entire cohort, median survival of patients with and without TP53
      mutations was 1·0 and 6·7 years respectively (P < 0·001).
    explanation: The cohort supports the adverse association of TP53-altered ATL.
  - reference: PMID:16569765
    reference_title: "Persistent inhibition of telomerase reprograms adult T-cell leukemia to p53-dependent senescence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While ATL patients carrying a wild-type p53 enter remission following
      treatment with AZT, those with a mutated p53 did not respond, and
      patients' disease relapse was associated with the selection of a tumor
      clone carrying mutated inactive p53.
    explanation: Patient response and relapse data support mutated TP53 as a treatment-context selected somatic driver.
- name: CCR4
  gene_term:
    preferred_term: CCR4
    term:
      id: hgnc:1605
      label: CCR4
  association: Recurrent somatic gain-of-function mutation in a subset of ATL
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  notes: >-
    Truncating CCR4 variants occurred in 14 of 53 samples and experimentally
    increased ligand-directed migration and PI3K-AKT signaling. CCR4 expression,
    rather than mutation status, is the treatment-selection concept for
    mogamulizumab in the cited trial.
  evidence:
  - reference: PMID:25488980
    reference_title: "Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted
      exclusively of nonsense or frameshift mutations that truncated the coding
      region at C329, Q330, or Y331 in the carboxy terminus.
    explanation: Patient-tumor sequencing establishes recurrent truncating CCR4 variants.
  - reference: PMID:25488980
    reference_title: "Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functionally, the CCR4-Q330 nonsense isoform was gain-of-function because
      it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in
      part by impairing receptor internalization.
    explanation: Functional assays establish gain of function for a recurrent truncating isoform.
  - reference: PMID:26437031
    reference_title: "Integrated molecular analysis of adult T cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other notable features include a predominance of activating mutations (in
      PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions
      (CTLA4-CD28 and ICOS-CD28).
    explanation: Integrated profiling of 426 ATL cases independently identifies CCR4 among recurrent activating alterations.
diagnosis:
- name: HTLV-1 Serology with Malignant T-Cell Confirmation
  diagnosis_term:
    preferred_term: serology testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    Anti-HTLV-1 seropositivity documents infection but supports ATL only in a
    compatible malignant mature T-cell clinicopathologic context.
  results: Anti-HTLV-1 antibodies are detected.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, the diagnosis of ATL is made based on seropositivity for
      HTLV-1 and histologically and/or cytologically proven peripheral T cell
      lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1
      carriers have been reported
    explanation: The review requires infection evidence to be combined with malignant-cell confirmation and notes the carrier-state specificity limitation.
- name: Histologic or Cytologic Confirmation of Peripheral T-Cell Malignancy
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Histologic or cytologic examination must establish a compatible peripheral
    T-cell malignancy in the HTLV-1-seropositive patient.
  results: Compatible malignant peripheral T cells are demonstrated histologically or cytologically.
  evidence:
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, the diagnosis of ATL is made based on seropositivity for
      HTLV-1 and histologically and/or cytologically proven peripheral T cell
      lymphoma (PTCL), although rare cases of other PTCL developing in HTLV-1
      carriers have been reported
    explanation: The review explicitly requires pathologic malignant-cell confirmation alongside HTLV-1 seropositivity.
- name: Clonal HTLV-1 Proviral Integration Analysis
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Southern blot analysis can demonstrate clonal HTLV-1 proviral integration
    in tumor cells as biologic confirmation.
  results: A clonally integrated HTLV-1 provirus in tumor cells biologically supports ATL.
  evidence:
  - reference: PMID:15129647
    reference_title: "HTLV-1 and associated adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The demonstration by Southern blot analysis of the clonal integration of
      an HTLV-1 provirus in the tumoral cells represents the gold-standard to
      define biologically ATLL.
    explanation: The review defines this molecular finding as biologic confirmation of ATL.
- name: Shimoyama Clinical Subtype Classification
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Clinical and laboratory findings are used to assign acute, lymphoma,
    chronic, or smoldering ATL; the original cohort documented distinct clinical
    features and markedly different survival across these subtypes.
  results: The presentation is assigned to one of four clinicopathologic subtypes.
  evidence:
  - reference: PMID:1751370
    reference_title: "Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The following diagnostic criteria are proposed to classify four clinical
      subtypes of HTLV-1 associated adult T-cell leukaemia-lymphoma (ATL)
    explanation: The 818-patient classification study establishes the four-subtype framework.
treatments:
- name: Chemotherapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Systemic chemotherapy produced a 49% overall response rate in the cited
    aggressive-ATL cohort; this entry does not extrapolate to every named
    regimen or duration of response.
  evidence:
  - reference: PMID:22042945
    reference_title: "Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall response rate ranged from 49% with chemotherapy alone to 81%
      with combined first-line therapy (chemotherapy with concurrent/sequential
      ZDV/IFN-α).
    explanation: >-
      Study shows chemotherapy alone achieves 49% response rate in aggressive
      ATLL, supporting modest efficacy.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  target_mechanisms:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    treatment_effect: INHIBITS
    description: Cytotoxic chemotherapy reduces clinically measurable malignant ATL burden.
    evidence:
    - reference: PMID:22042945
      reference_title: "Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The overall response rate ranged from 49% with chemotherapy alone to 81%
        with combined first-line therapy (chemotherapy with concurrent/sequential
        ZDV/IFN-α).
      explanation: Clinical response indirectly supports inhibition of malignant clonal burden.
- name: Mogamulizumab
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Mogamulizumab is a defucosylated anti-CCR4 monoclonal antibody approved in
    Japan for relapsed or refractory CCR4-positive ATL. The cited evidence does
    not establish CCR4 mutation as a response requirement.
  evidence:
  - reference: PMID:30573506
    reference_title: "Mogamulizumab versus investigator's choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mogamulizumab treatment resulted in 11% cORR, with a tolerable safety
      profile.
    explanation: >-
      The international phase II trial reported an 11% composite overall
      response rate with a tolerable safety profile.
  - reference: PMID:30573506
    reference_title: "Mogamulizumab versus investigator's choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mogamulizumab is approved in Japan for the treatment of relapsed/refractory
      CCR4+ ATL on the basis of a phase II trial showing a 50% overall response
      rate (ORR) in a relapsed population.
    explanation: The trial report directly supports the Japan-specific approval statement.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: mogamulizumab
      term:
        id: NCIT:C62510
        label: Mogamulizumab
  target_mechanisms:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    treatment_effect: INHIBITS
    description: CCR4 binding and enhanced ADCC target CCR4-positive ATL tumor cells.
    evidence:
    - reference: PMID:30573506
      reference_title: "Mogamulizumab versus investigator's choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mogamulizumab is a first-in-class defucosylated humanized IgG1 kappa
        monoclonal antibody that selectively binds to CCR4 and has enhanced
        antibody-dependent cellular cytotoxicity (ADCC) activity.
      explanation: The trial report supports CCR4-positive tumor-cell targeting through binding and ADCC.
- name: Allogeneic Stem Cell Transplantation
  action_category: THERAPEUTIC
  therapeutic_modality: CELL_THERAPY
  description: >-
    Allogeneic hematopoietic stem-cell transplantation can provide selected
    transplant-eligible patients with aggressive ATL a chance of long-term
    remission through a graft-versus-ATL effect.
  evidence:
  - reference: PMID:30573506
    reference_title: "Mogamulizumab versus investigator's choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic stem cell transplantation (allo-SCT) can significantly prolong
      survival, but there are few appropriate candidates
    explanation: >-
      The study states that allo-SCT can prolong survival while noting that few
      patients are appropriate candidates.
  - reference: DOI:10.3389/fmicb.2020.01207
    reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thus, allo-HSCT can provide a chance of long-term remission through a
      graft- versus-ATL (GvATL) effect
    explanation: The treatment review supports the bounded long-term-remission and GvATL claims.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Malignant CD4-Positive T-Cell Clonal Expansion
    treatment_effect: INHIBITS
    description: The graft-versus-ATL effect can suppress the malignant ATL clone.
    evidence:
    - reference: DOI:10.3389/fmicb.2020.01207
      reference_title: "Diagnostic Approaches and Established Treatments for Adult T Cell Leukemia Lymphoma"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Thus, allo-HSCT can provide a chance of long-term remission through a
        graft- versus-ATL (GvATL) effect
      explanation: The graft-versus-ATL effect supports clonal inhibition without resolving every immune effector step.
- name: Interferon-alpha and Zidovudine
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Zidovudine plus interferon-alpha was associated with prolonged survival in
    acute and lymphoma ATL in the cited retrospective cohort. No molecular
    treatment-target edge is asserted from survival evidence alone.
  evidence:
  - reference: PMID:22042945
    reference_title: "Use of zidovudine and interferon alfa with chemotherapy improves survival in both acute and lymphoma subtypes of adult T-cell leukemia/lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and
      lymphoma ATLL (P < .001) and was the sole factor associated with
      reduction in risk of death in aggressive ATLL
    explanation: >-
      UK study demonstrated ZDV/IFN-α significantly prolonged survival in both
      acute and lymphoma ATLL subtypes.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant interferon alfa
      term:
        id: NCIT:C225
        label: Recombinant Interferon Alfa
    - preferred_term: zidovudine
      term:
        id: CHEBI:10110
        label: zidovudine
disease_term:
  preferred_term: adult T-cell leukemia/lymphoma
  term:
    id: MONDO:0019471
    label: adult T-cell leukemia/lymphoma

classifications:
  icdo_morphology:
    classification_value: Lymphoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
  nih_research_priority:
  - classification_value: NIH_HT_42_rare_cancers_across_cancer_control_continuum
    notes: Rare HTLV-1-driven mature T-cell leukemia/lymphoma — flagship rare-cancer exemplar for NIH Highlighted Topic 42 (rare cancers across the cancer control continuum).
references:
- reference: DOI:10.1111/cas.13343
  title: 'Mogamulizumab for relapsed adult T‐cell leukemia–lymphoma: Updated follow‐up analysis of phase I and <scp>II</scp> studies'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody.
    supporting_text: The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody.
    evidence:
    - reference: DOI:10.1111/cas.13343
      reference_title: 'Mogamulizumab for relapsed adult T‐cell leukemia–lymphoma: Updated follow‐up analysis of phase I and <scp>II</scp> studies'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.1111/ejh.12863
  title: Effects of mogamulizumab in adult T‐cell leukemia/lymphoma in clinical practice
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study.
    supporting_text: The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study.
    evidence:
    - reference: DOI:10.1111/ejh.12863
      reference_title: Effects of mogamulizumab in adult T‐cell leukemia/lymphoma in clinical practice
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.1182/blood-2011-03-345702
  title: How I treat adult T-cell leukemia/lymphoma
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I.
    supporting_text: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I.
    evidence:
    - reference: DOI:10.1182/blood-2011-03-345702
      reference_title: How I treat adult T-cell leukemia/lymphoma
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.1182/bloodadvances.2020003053
  title: 'Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: 'Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study'
    supporting_text: Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696).
    evidence:
    - reference: DOI:10.1182/bloodadvances.2020003053
      reference_title: 'Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696).
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.1186/s12985-023-02077-0
  title: 'Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy.
    supporting_text: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy.
    evidence:
    - reference: DOI:10.1186/s12985-023-02077-0
      reference_title: 'Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.3390/biom13101543
  title: 'Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL).
    supporting_text: Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL).
    evidence:
    - reference: DOI:10.3390/biom13101543
      reference_title: 'Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL).
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.3390/medicina60060872
  title: 'Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1).
    supporting_text: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1).
    evidence:
    - reference: DOI:10.3390/medicina60060872
      reference_title: 'Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1).
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.3390/v16101616
  title: Current State of Therapeutics for HTLV-1
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally.
    supporting_text: Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally.
    evidence:
    - reference: DOI:10.3390/v16101616
      reference_title: Current State of Therapeutics for HTLV-1
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.3390/v17050664
  title: 'Human T-Lymphotropic Virus (HTLV): Epidemiology, Genetic, Pathogenesis, and Future Challenges'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types.
    supporting_text: Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types.
    evidence:
    - reference: DOI:10.3390/v17050664
      reference_title: 'Human T-Lymphotropic Virus (HTLV): Epidemiology, Genetic, Pathogenesis, and Future Challenges'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
- reference: DOI:10.3390/v17101333
  title: 'HTLV-1 and ATLL: Epidemiology, Oncogenesis, and Opportunities for Community-Informed Research in the United States'
  found_in:
  - Adult_T_Cell_Leukemia_Lymphoma-deep-research-falcon.md
  findings:
  - statement: 'HTLV-1 and ATLL: Epidemiology, Oncogenesis, and Opportunities for Community-Informed Research in the United States'
    supporting_text: Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year.
    evidence:
    - reference: DOI:10.3390/v17101333
      reference_title: 'HTLV-1 and ATLL: Epidemiology, Oncogenesis, and Opportunities for Community-Informed Research in the United States'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year.
      explanation: Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
datasets:
- accession: ega:EGAS00001001210
  title: Whole Genome sequencing of adult T-cell leukemia/lymphoma
  description: Whole Genome sequencing of a single adult T-cell leukemia/lymphoma case
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001296
  title: Integrated molecular analysis of adult T-cell leukemia/lymphoma
  description: This study is an integrated molecular study of adult T-cell leukemia/lymphoma which includes whole-exome (n = 81), whole-genome (n = 48), and transcriptome sequencing data (n = 57) as well as methylation (n = 109) and SNP array data (n = 426)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003575
  title: RNA-sequencing of adult T-cell leukemia/lymphoma samples
  description: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. In this study, we performed RNA-sequencing (RNA-seq) analysis for ATL samples including 9 primary tumors and 1 ATL cell line to clarify gene expression profiles in this disease.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Adult T-Cell Leukemia/Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
📚

References & Deep Research

References

10
DOI:10.1111/cas.13343
Mogamulizumab for relapsed adult T‐cell leukemia–lymphoma: Updated follow‐up analysis of phase I and <scp>II</scp> studies
1 finding
The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody.
"The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody."
Show evidence (1 reference)
DOI:10.1111/cas.13343 SUPPORT Human Clinical
"The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.1111/ejh.12863
Effects of mogamulizumab in adult T‐cell leukemia/lymphoma in clinical practice
1 finding
The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study.
"The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study."
Show evidence (1 reference)
DOI:10.1111/ejh.12863 SUPPORT Human Clinical
"The efficacy of mogamulizumab in adult T‐cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.1182/blood-2011-03-345702
How I treat adult T-cell leukemia/lymphoma
1 finding
Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I.
"Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I."
Show evidence (1 reference)
DOI:10.1182/blood-2011-03-345702 SUPPORT Other
"Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.1182/bloodadvances.2020003053
Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study
1 finding
Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study
"Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696)."
Show evidence (1 reference)
DOI:10.1182/bloodadvances.2020003053 SUPPORT Human Clinical
"Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696)."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.1186/s12985-023-02077-0
Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis
1 finding
ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy.
"ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy."
Show evidence (1 reference)
DOI:10.1186/s12985-023-02077-0 SUPPORT Other
"ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.3390/biom13101543
Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review
1 finding
Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL).
"Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL)."
Show evidence (1 reference)
DOI:10.3390/biom13101543 SUPPORT Other
"Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL)."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.3390/medicina60060872
Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country
1 finding
Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1).
"Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1)."
Show evidence (1 reference)
DOI:10.3390/medicina60060872 SUPPORT Human Clinical
"Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1)."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.3390/v16101616
Current State of Therapeutics for HTLV-1
1 finding
Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally.
"Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally."
Show evidence (1 reference)
DOI:10.3390/v16101616 SUPPORT Other
"Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.3390/v17050664
Human T-Lymphotropic Virus (HTLV): Epidemiology, Genetic, Pathogenesis, and Future Challenges
1 finding
Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types.
"Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types."
Show evidence (1 reference)
DOI:10.3390/v17050664 SUPPORT Other
"Human T-lymphotropic viruses (HTLVs) are deltaretroviruses infecting millions of individuals worldwide, with HTLV-1 and HTLV-2 being the most widespread and clinically relevant types."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.
DOI:10.3390/v17101333
HTLV-1 and ATLL: Epidemiology, Oncogenesis, and Opportunities for Community-Informed Research in the United States
1 finding
HTLV-1 and ATLL: Epidemiology, Oncogenesis, and Opportunities for Community-Informed Research in the United States
"Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year."
Show evidence (1 reference)
DOI:10.3390/v17101333 SUPPORT Other
"Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year."
Deep research cited this publication as relevant literature for Adult T Cell Leukemia Lymphoma.

Deep Research

1
Falcon ▸
Adult T-Cell Leukemia/Lymphoma (ATLL/ATL) — Disease Characteristics Research Report
Edison Scientific Literature 57 citations 2026-05-08T08:22:10.434085

Adult T-Cell Leukemia/Lymphoma (ATLL/ATL) — Disease Characteristics Research Report

Target Disease

  • Disease name: Adult T-cell leukemia/lymphoma (ATL/ATLL) (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2)
  • MONDO ID: Not retrieved in this run
  • Category: Mature T-cell neoplasm / peripheral T-cell lymphoma-leukemia, HTLV-1–associated (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2)

1. Disease Information

1.1 Concise overview

Adult T-cell leukemia/lymphoma (ATLL; also written ATL) is a distinct mature/peripheral T-cell malignancy etiologically caused by human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2). It typically develops after a long latency (≈20–30 years) in a minority of HTLV-1 carriers and is characterized by aggressive clinical behavior in acute and lymphoma subtypes, with frequent immunosuppression and opportunistic infections (altieri2025htlv1andatll pages 7-9).

Abstract quote (etiology/risk): “Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). … 5–10% of carriers lose this balance and develop ATL.” (Nakahata et al., Biomolecules, 2023-10; (nakahata2023understandingtheimmunopathology pages 1-2)).

1.2 Key identifiers and synonyms

Key naming and identifier fields available from retrieved evidence are summarized here:

Field Value Evidence / notes ICD-10 ICD-11 MeSH MONDO Orphanet OMIM
Preferred disease name Adult T-cell leukemia/lymphoma Distinct mature/peripheral T-cell malignancy caused by HTLV-1; often abbreviated ATL or ATLL (tsukasaki2020diagnosticapproachesand pages 1-2, nosaka2025jshpracticalguidelines pages 1-3) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Concise disease overview Aggressive mature T-cell neoplasm arising after long-latency HTLV-1 infection, with leukemic and/or lymphomatous presentations Reviews/guidelines describe ATL as HTLV-1-caused, typically after decades of latency; median survival for aggressive disease remains poor (altieri2025htlv1andatll pages 7-9, nakahata2023understandingtheimmunopathology pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Common abbreviations ATL; ATLL Both forms are used in recent literature and guidelines (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Key synonyms / alternative names Adult T-cell leukaemia-lymphoma; Adult T-cell leukemia-lymphoma; HTLV-1-associated adult T-cell leukemia/lymphoma British and American spellings both appear; disease is frequently described as HTLV-1-associated ATL/ATLL (o’donnell2023integratedmolecularand pages 3-4, tsukasaki2020diagnosticapproachesand pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Causative agent Human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) Causal viral etiology is consistently stated across guideline and reviews (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2, nakahata2023understandingtheimmunopathology pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Typical target cell / lineage Mature CD4+ T-cell neoplasm; commonly CD3+, CD4+, CD25+, often CCR4+ Immunophenotypic description from overview/review sources (altieri2025htlv1andatll pages 7-9, tsukasaki2020diagnosticapproachesand pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Canonical clinical classification Four Shimoyama subtypes: acute, lymphoma, chronic, smoldering Current guideline retains Shimoyama clinical subtyping; acute/lymphoma and unfavorable chronic are aggressive, favorable chronic and smoldering are indolent (nosaka2025jshpracticalguidelines pages 1-3, altieri2025htlv1andatll pages 7-9, nosaka2025jshpracticalguidelines media 8f3eac9b) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Aggressive vs indolent grouping Aggressive: acute, lymphoma, chronic with unfavorable factors; Indolent: chronic without unfavorable factors, smoldering Unfavorable chronic defined by abnormal BUN, LDH, or low albumin in guideline summary (nosaka2025jshpracticalguidelines pages 1-3) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Latency / temporal development Usually develops after long latency, about 20-30 years after HTLV-1 infection; many carriers remain asymptomatic for decades Long latency emphasized in recent reviews; only a minority of carriers progress to ATL/ATLL (altieri2025htlv1andatll pages 7-9, o’donnell2023integratedmolecularand pages 3-4, nakahata2023understandingtheimmunopathology pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run
Mode of knowledge represented here Aggregated disease-level literature and guidelines, not individual-patient EHR data Information in this summary comes from reviews, consensus/guideline documents, and cohort studies (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2, iordan2024clinicalfeaturesand pages 1-2) Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run Not retrieved in this run

Table: This table summarizes the core disease naming, etiology, subtype classification, and latency concepts for adult T-cell leukemia/lymphoma. Identifier fields are included for ontology/database curation and marked as not retrieved where this evidence run did not supply them.

Note: ICD-10/ICD-11/MeSH/MONDO/Orphanet/OMIM codes were not directly retrieved from the full text evidence in this tool run; they should be added via targeted ontology/registry queries.

1.3 Evidence sources represented in this report

This report is derived from aggregated disease-level resources: reviews, guidelines/consensus documents, clinical trials, and cohort studies (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2, iordan2024clinicalfeaturesand pages 1-2). It does not include individual EHR-derived patient records.

2. Etiology

2.1 Primary causes

ATLL is causally linked to HTLV-1 infection, a deltaretrovirus that persists via proviral integration and clonal expansion of infected T cells (nosaka2025jshpracticalguidelines pages 1-3, o’donnell2023integratedmolecularand pages 2-3). Viral proteins Tax and HBZ contribute to oncogenesis and immune dysregulation (o’donnell2023integratedmolecularand pages 3-4, nakahata2023understandingtheimmunopathology pages 1-2).

2.2 Risk factors

Infectious exposure and transmission routes: Major transmission routes include mother-to-child via breastfeeding, sexual contact, and exposure to infected blood products/transfusion (tsukasaki2020diagnosticapproachesand pages 1-2, branda2025humantlymphotropicvirus pages 10-12).

High proviral load: In a 2023 Lancet Haematology review, higher baseline proviral load strongly predicted ATLL risk; proviral load “>4 copies per 100 PBMCs” was associated with HR 3.57 (95% CI 2.25–5.68) for developing ATLL (o’donnell2023integratedmolecularand pages 3-4).

Coinfection/host immune state: Strongyloides coinfection is cited as promoting ATLL development, consistent with the concept that immune status influences progression (nakahata2023understandingtheimmunopathology pages 1-2).

2.3 Protective factors

Evidence in this run supports breastfeeding modification as protective against HTLV-1 transmission (see Prevention). Specific genetic protective variants were not retrieved as explicit “protective variants” in the excerpts, although host HLA influences transmission risk and immune control (o’donnell2023integratedmolecularand pages 2-3).

2.4 Gene–environment interactions

Host genetics (e.g., HLA concordance between mother and infant) influences HTLV-1 transmission risk, modifying how an environmental exposure (breastfeeding) translates into infection (o’donnell2023integratedmolecularand pages 2-3).

3. Phenotypes

3.1 Clinical subtypes and defining features (Shimoyama)

ATLL is classically divided into acute, lymphoma, chronic, and smoldering subtypes (nosaka2025jshpracticalguidelines pages 1-3, nosaka2025jshpracticalguidelines media 8f3eac9b). A 2023 Lancet Haematology review provides quantitative subtype proportions: smouldering (5–10%), chronic (10–20%), lymphoma (20–25%), with acute accounting for the remainder (o’donnell2023integratedmolecularand pages 5-6).

Smouldering ATL is defined by specific blood and laboratory thresholds: “presence of abnormal T cells with flower cell morphology in peripheral blood (≥5%)”, normal lymphocyte count (≤4×10^9/L), “no hypercalcaemia (corrected calcium concentration <2·74 mmol/L)”, and only mild LDH elevation (o’donnell2023integratedmolecularand pages 5-6).

3.2 Common symptoms/signs and lab abnormalities

Across guidelines and reviews, common features include: - Leukocytosis with abnormal “flower cells” (nosaka2025jshpracticalguidelines pages 1-3) - Lymphadenopathy, hepatosplenomegaly, skin rash/skin lesions (nosaka2025jshpracticalguidelines pages 1-3, altieri2025htlv1andatll pages 7-9) - Elevated LDH, hypercalcemia (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2) - Opportunistic infections (e.g., Pneumocystis, aspergillosis, candidiasis, CMV; also Strongyloides) (altieri2025htlv1andatll pages 7-9, nosaka2025jshpracticalguidelines pages 1-3)

Real-world complications documented in a 2024 Romanian cohort included cytopenias and infections in all patients; pathogens included Candida albicans, C. difficile, bacterial infections, herpes zoster, SARS-CoV-2, CMV reactivation, and BK virus; symptomatic hypercalcemia was common (iordan2024clinicalfeaturesand pages 5-6).

3.3 Suggested HPO terms (examples)

(These are ontology suggestions; IDs should be verified against HPO.) - Hypercalcemia (HP:0003072) (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2) - Lymphadenopathy (HP:0002716) (nosaka2025jshpracticalguidelines pages 1-3) - Hepatosplenomegaly (HP:0001433 / HP:0001744) (nosaka2025jshpracticalguidelines pages 1-3) - Skin rash / Cutaneous lesion (HP:0000988 / HP:0000951) (nosaka2025jshpracticalguidelines pages 1-3) - Elevated lactate dehydrogenase (HP:0003236) (nosaka2025jshpracticalguidelines pages 1-3) - Opportunistic infection (HP:0002719) (altieri2025htlv1andatll pages 7-9, nosaka2025jshpracticalguidelines pages 1-3) - Leukocytosis (HP:0001974) (nosaka2025jshpracticalguidelines pages 1-3)

3.4 Quality-of-life impact

Direct QoL instrument data (EQ-5D/SF-36/PROMIS) were not retrieved in this run; however, severe systemic symptoms, infections, and hypercalcemia complications in aggressive ATLL imply major functional and hospitalization burden (iordan2024clinicalfeaturesand pages 5-6).

4. Genetic/Molecular Information

4.1 Viral oncogenes and host alterations (core concepts)

Two viral gene products are repeatedly emphasized: - Tax: transiently expressed, highly immunogenic, drives proliferation/anti-apoptotic pathways and host gene dysregulation (o’donnell2023integratedmolecularand pages 3-4, nakahata2023understandingtheimmunopathology pages 1-2). - HBZ: persistently expressed antisense product with low immunogenicity; promotes clonal proliferation and immune evasion (o’donnell2023integratedmolecularand pages 3-4, o’donnell2023integratedmolecularand pages 2-3).

Abstract quote (Tax oncogenesis): “HTLV-1 encodes the viral transcription transactivator, Tax, in the pX region of its genome, which promotes oncogenesis.” (Nakahata et al., Biomolecules, 2023-10; (nakahata2023understandingtheimmunopathology pages 1-2)).

4.2 Somatic genomic/epigenetic alterations (host)

From a 2023 immunopathology review: - “~90% of ATL cases have activating TCR–NF-κB pathway mutations” (nakahata2023understandingtheimmunopathology pages 3-5). - “~40% show CpG island hypermethylation (CIMP)” (nakahata2023understandingtheimmunopathology pages 3-5). - HLA class I mutations/deletions and PD-L1 3′-UTR structural alterations that increase PD-L1 mRNA are enriched in ATL (nakahata2023understandingtheimmunopathology pages 3-5).

Single-cell features described include upregulation of immunosuppressive molecules (PD-L1, CD73, CD39) and activation markers (CD71, CD25, CD38) (nakahata2023understandingtheimmunopathology pages 3-5).

4.3 Suggested gene/protein targets for annotation

  • CCR4 (target of mogamulizumab) (ishida2017mogamulizumabforrelapsed pages 1-2)
  • PD-L1 (CD274) structural alterations and overexpression (nakahata2023understandingtheimmunopathology pages 3-5)
  • FOXP3 (Treg phenotype association) (nakahata2023understandingtheimmunopathology pages 3-5)

4.4 Suggested GO biological process terms (examples)

(IDs should be verified against GO.) - NF-κB signaling (nakahata2023understandingtheimmunopathology pages 3-5, o’donnell2023integratedmolecularand pages 3-4) - Regulation of T-cell activation / TCR signaling (nakahata2023understandingtheimmunopathology pages 3-5) - Immune evasion / negative regulation of immune response (nakahata2023understandingtheimmunopathology pages 3-5, o’donnell2023integratedmolecularand pages 3-4) - DNA methylation / epigenetic gene regulation (nakahata2023understandingtheimmunopathology pages 3-5)

4.5 Suggested CL (Cell Ontology) terms

  • CD4-positive, alpha-beta T cell (ATL cell of origin/target) (o’donnell2023integratedmolecularand pages 2-3)
  • Regulatory T cell (Treg-like phenotype; FOXP3-associated) (nakahata2023understandingtheimmunopathology pages 3-5, o’donnell2023integratedmolecularand pages 3-4)
  • Cytotoxic CD8-positive T cell (Tax-specific CTLs in immune control) (o’donnell2023integratedmolecularand pages 3-4)

5. Environmental Information

5.1 Infectious agent

HTLV-1 is the infectious agent underlying ATLL (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2).

5.2 Lifestyle/environmental exposures

In this run, the key non-genetic exposures relate to transmission opportunities: breastfeeding, sexual exposure, contaminated blood/organ products, and injection-related exposures (altieri2025htlv1andatll pages 12-14, tsukasaki2020diagnosticapproachesand pages 1-2).

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

1) HTLV-1 acquisition (breastfeeding/sexual/blood) → 2) proviral integration and clonal expansion of infected CD4+ T cells with generally quiescent transcription → 3) episodic Tax expression enables spread and promotes proliferative programs but drives immune recognition → 4) selection for immune escape with Tax silencing (e.g., 5′ LTR methylation/deletion) and persistence via HBZ-driven proliferation → 5) accumulation of host genetic and epigenetic lesions (e.g., TCR–NF-κB pathway mutations, CIMP, HLA/PD-L1 alterations) → 6) emergence of malignant clone with immune evasion and systemic immunodeficiency → clinical ATLL with hypercalcemia, organ infiltration, and opportunistic infections (o’donnell2023integratedmolecularand pages 3-4, nakahata2023understandingtheimmunopathology pages 3-5, nosaka2025jshpracticalguidelines pages 1-3).

6.2 Key mechanisms and pathways

  • Tax-driven activation of proliferative and anti-apoptotic pathways; selection for Tax-silenced clones due to immune pressure (o’donnell2023integratedmolecularand pages 3-4, nakahata2023understandingtheimmunopathology pages 1-2).
  • HBZ-driven clonal proliferation and immune evasion (low immunogenicity), with promotion of tolerogenic/Treg-like phenotypes (o’donnell2023integratedmolecularand pages 3-4, o’donnell2023integratedmolecularand pages 2-3).
  • TCR–NF-κB pathway mutations in most cases (nakahata2023understandingtheimmunopathology pages 3-5).
  • Immune checkpoint and antigen presentation alterations: PD-L1 structural alterations and HLA class I changes contribute to immune escape (nakahata2023understandingtheimmunopathology pages 3-5).

6.3 Molecular profiling (selected)

Single-cell transcriptomic observations include ATL cell upregulation of PD-L1, CD73, CD39, CD71, CD25, CD38, and dynamic HLA class II expression patterns during clonal expansion (nakahata2023understandingtheimmunopathology pages 3-5).

7. Anatomical Structures Affected

7.1 Organ-level involvement

  • Blood and bone marrow (leukemic manifestations in acute/chronic) (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2)
  • Lymph nodes (lymphoma subtype and systemic disease) (nosaka2025jshpracticalguidelines pages 1-3)
  • Skin (skin lesions/rash; common) (nosaka2025jshpracticalguidelines pages 1-3, tsukasaki2020diagnosticapproachesand pages 1-2)
  • Liver/spleen (hepatosplenomegaly) (nosaka2025jshpracticalguidelines pages 1-3)
  • CNS/GI involvement can occur, particularly noted for acute subtype (tsukasaki2020diagnosticapproachesand pages 1-2)

7.2 Suggested UBERON terms (examples)

(IDs should be verified against UBERON.) - Peripheral blood; bone marrow; lymph node; skin; liver; spleen; central nervous system; gastrointestinal tract (tsukasaki2020diagnosticapproachesand pages 1-2, nosaka2025jshpracticalguidelines pages 1-3).

8. Temporal Development

ATLL typically develops after long latency from infection (20–30 years) (altieri2025htlv1andatll pages 7-9). Aggressive subtypes have a rapid course (months), while indolent subtypes have longer median survivals (years) (nosaka2025jshpracticalguidelines pages 1-3, o’donnell2023integratedmolecularand pages 5-6).

9. Inheritance and Population

9.1 Epidemiology and demographics

  • HTLV-1 carriers: estimated ~10–20 million worldwide; Japan ~1.08 million carriers (nosaka2025jshpracticalguidelines pages 1-3).
  • Lifetime risk of ATLL among carriers: ~2–5% (Japan guideline) (nosaka2025jshpracticalguidelines pages 1-3); another recent review states ATLL occurs in ~3–5% of HTLV-1 infections (altieri2025htlv1andatll pages 7-9).
  • Subtype frequencies in Japan (2012–2013): acute 51.9%, lymphoma 24.9%, chronic 12.5%, smoldering 10.7% (nosaka2025jshpracticalguidelines pages 1-3).

10. Diagnostics

10.1 Diagnostic criteria and subtype classification

Table 1 from the JSH guideline provides ATL diagnostic and subtype classification criteria and can be used as the primary structured reference for smoldering/chronic/lymphoma/acute definitions in routine practice (nosaka2025jshpracticalguidelines media 8f3eac9b).

10.2 Laboratory and pathology tests

HTLV-1 confirmation: The guideline states serology positive by particle agglutination, ELISA/Western blotting, or line immunoassay; confirmatory tests are recommended (nosaka2025jshpracticalguidelines pages 1-3). Where available, “Institutions capable of performing Southern blotting should do so to confirm integration of HTLV-1 provirus into ATL cells.” (nosaka2025jshpracticalguidelines pages 1-3).

Molecular assays: PCR/qPCR proviral testing and clonality analysis are referenced as diagnostic approaches (branda2025humantlymphotropicvirus pages 17-17, stUnknownyearprotocolforthe pages 5-10).

Immunophenotyping (flow cytometry): Recommended minimal panel includes CD3, CD4, CD7, CD8, CD25; typical tumor phenotype includes CD2/CD4/CD5/CD45RO/CD29/TCR with reduced CD3 and often negative for CD7, CD8, CD26 (bazarbachi2011howitreat pages 2-3).

Histology requirement at low blood tumor burden: When circulating abnormal lymphocytes are <5%, histological confirmation of neoplastic lesions is required for smoldering/chronic/acute ATL diagnosis (nosaka2025jshpracticalguidelines pages 1-3).

11. Outcome/Prognosis

11.1 Survival statistics (recent guideline + recent review)

From a nationwide Japan survey (2010–2011) summarized in the JSH guideline: - 4-year OS: acute 16.8%, lymphoma 19.6%, chronic unfavorable 26.6%, chronic favorable 62.1%, smoldering 59.8% (nosaka2025jshpracticalguidelines pages 1-3).

From a 2023 Lancet Haematology review (median OS): - Smouldering: median OS 55 months; 4-year OS 52% (o’donnell2023integratedmolecularand pages 5-6) - Chronic: median OS 31.5 months; 4-year OS 36% (o’donnell2023integratedmolecularand pages 5-6)

A Japanese cohort (2000–2009) reported median OS: acute 8.3 months; lymphoma 10.6 months; chronic 31.5 months; smoldering 55.0 months (munakata2018adulttcellleukemialymphoma. pages 12-14).

11.2 Real-world outcomes (2024)

A 2024 Romanian single-center cohort of aggressive ATLL reported median survival 6.37 months overall; lymphoma-type 8.16 months vs acute-type 3.60 months, with low response to chemotherapy (iordan2024clinicalfeaturesand pages 1-2).

12. Treatment

12.1 Established and emerging treatments (with quantitative outcomes)

A consolidated treatment evidence table from this run is provided here:

Treatment modality Setting Key efficacy statistics Safety / limitations Publication year URL / DOI Evidence
Zidovudine + interferon-α (AZT/IFN) Frontline, combination with chemotherapy, maintenance in selected subtypes 2023 meta-analysis of 15 studies/1,101 patients: overall response 67% (95% CI 0.50–0.80), CR 33% (95% CI 0.24–0.44), PR 31% (95% CI 0.24–0.39); better responses when used front-line and in indolent disease; aggressive subtype pooled CR 25%, indolent pooled CR 53%; one observational analysis reported HR for death 0.23 (95% CI 0.09–0.60) in aggressive ATLL; one report cited median PFS 48 months with AZT/IFN vs 11 months after chemotherapy in CR patients Evidence base is heterogeneous and largely non-randomized; interferon availability issues noted; some cohorts reported no significant survival difference vs chemotherapy; detailed pooled AE statistics not robustly available in retrieved evidence 2023 https://doi.org/10.1186/s12985-023-02077-0 (shafiee2023zidovudineandinterferon pages 1-2, shafiee2023zidovudineandinterferon pages 4-6, shafiee2023zidovudineandinterferon pages 8-9, shafiee2023zidovudineandinterferon pages 6-7, shafiee2023zidovudineandinterferon pages 7-8)
Intensive multiagent chemotherapy (e.g., VCAP-AMP-VECP, modified LSG15, CHOP/CHOP-like, hyper-CVAD) Frontline for aggressive acute/lymphoma ATL In randomized phase II study, adding mogamulizumab to mLSG15 increased CR to 52% vs 33% with mLSG15 alone and ORR to 86% vs 75%; Romanian real-world cohort using CHOP/CHOP-like, modified LSG15, or hyper-CVAD had only 6 responses among 20 patients and median survival 6.37 months overall (8.16 months lymphoma-type, 3.60 months acute-type) Conventional chemotherapy responses are often short; poor outcomes in aggressive disease; cytopenias/infections common in real-world practice 2015, 2024 https://doi.org/10.1111/bjh.13338 ; https://doi.org/10.3390/medicina60060872 (iordan2024clinicalfeaturesand pages 1-2, iordan2024clinicalfeaturesand pages 9-10, iordan2024clinicalfeaturesand pages 2-4)
Mogamulizumab monotherapy Relapsed/refractory aggressive ATL; also used prospectively in broader ATL population Phase II relapsed aggressive ATL: median PFS 5.2 months, 1-year PFS 26%, median OS 14.4 months, 3-year OS 23%; outcomes better with rash ≥grade 2: median PFS 11.7 months, median OS 25.6 months; multicenter observational study: ORR 65%, median PFS 7.4 months, median OS 16.0 months; retrospective real-world cohort: ORR 36%, CR 17%, median PFS 1.8 months, OS 4.0 months overall, better with ≥5 courses Rash is common and may correlate with response; fatal AEs reported; severe cutaneous reactions, HBV reactivation, infusion reactions reported; efficacy varies substantially by population and line of therapy 2017, 2020 https://doi.org/10.1111/cas.13343 ; https://doi.org/10.1182/bloodadvances.2020003053 ; https://doi.org/10.1111/ejh.12863 (ishida2017mogamulizumabforrelapsed pages 1-2, sekine2017effectsofmogamulizumab pages 14-18, sekine2017effectsofmogamulizumab pages 10-14, yonekura2020mogamulizumabforadult pages 12-12)
Mogamulizumab + intensive chemotherapy Frontline newly diagnosed aggressive ATL Randomized phase II: CR 52% (95% CI 33–71) and ORR 86% with mLSG15 + mogamulizumab vs CR 33% and ORR 75% with mLSG15 alone More grade ≥3 anemia, thrombocytopenia, lymphopenia, leukopenia, decreased appetite; CMV infection, interstitial lung disease, and skin disorders reported in combination arm 2015 https://doi.org/10.1111/bjh.13338 (wang2024currentstateof pages 12-14)
Mogamulizumab before allogeneic HSCT Pre-transplant exposure in transplant-eligible patients Not a benefit row: retrieved evidence emphasizes risk rather than efficacy Significantly increased risks of severe and steroid-refractory GVHD, non-relapse mortality, and overall mortality; 50-day washout before allo-HSCT recommended in 2024 review 2018, 2024 https://doi.org/10.1007/978-3-319-99716-2_7 ; https://doi.org/10.3390/v16101616 (wang2024currentstateof pages 34-35, wang2024currentstateof pages 12-14, munakata2018adulttcellleukemialymphoma. pages 16-17)
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) Consolidation/curative-intent for eligible aggressive ATL, typically early after remission/response Considered the only modality with curative potential in recent reviews/guidelines; exact pooled survival statistics not in retrieved 2023–2024 evidence here; Romanian cohort: only 2/20 patients underwent allo-HSCT Limited to fit/eligible patients; transplant morbidity/mortality substantial; timing complicated by prior mogamulizumab exposure 2023, 2024, 2025 https://doi.org/10.3390/biom13101543 ; https://doi.org/10.3390/v16101616 ; https://doi.org/10.3390/medicina60060872 ; https://doi.org/10.1007/s12185-025-04011-2 (nakahata2023understandingtheimmunopathology pages 2-3, nosaka2025jshpracticalguidelines pages 1-3, wang2024currentstateof pages 34-35, iordan2024clinicalfeaturesand pages 1-2, wang2024currentstateof pages 12-14)
Lenalidomide Relapsed/recurrent ATL; maintenance benefit discussed in review literature Mentioned as phase II ATLL-002 and case reports of maintenance benefit; no numeric ORR/PFS/OS values available in retrieved evidence Quantitative efficacy not in retrieved evidence; recognized as an approved/emerging option in reviews 2024 https://doi.org/10.3390/v16101616 (wang2024currentstateof pages 34-35)
Brentuximab vedotin Selected CD30-positive ATL; role discussed in reviews Not in retrieved evidence for quantitative efficacy statistics Mentioned as an approved/newer agent in review literature, but no trial outcome numbers captured in this run 2020 https://doi.org/10.3389/fmicb.2020.01207 (tsukasaki2020diagnosticapproachesand pages 1-2)
Valemetostat / EZH1/2-directed epigenetic therapy Relapsed/refractory ATL; investigational/early implementation Open-label single-arm phase II and preclinical activity mentioned; no numeric ORR/PFS/OS captured in retrieved evidence Early-phase/limited evidence in this run; quantitative outcomes not retrieved 2024 https://doi.org/10.3390/v16101616 (wang2024currentstateof pages 34-35)
Investigational CAR-T / gene-edited cell therapy (e.g., anti-CD7 CAR-T, CD70 allogeneic CRISPR-edited CAR-T) Relapsed/refractory T-cell malignancies including ATL in early-phase studies Trial programs identified: anti-CD7 CAR-T (NCT05620680; single-center phase 1, n=20) and CD70-directed allogeneic CRISPR-edited CTX131 (NCT06492304); efficacy statistics not in retrieved evidence Early-phase, small cohorts, relapsed/refractory setting; immune toxicity and translational challenges remain 2025 https://doi.org/10.1016/j.leukres.2025.107642 (epsteinpeterson2025newtreatmentsfor pages 15-15)
CRISPR/ZFN proviral excision / RNA-based or gene-therapy strategies Preclinical / future therapeutic modality No clinical efficacy statistics in retrieved evidence Delivery efficiency, off-target effects, and safety remain major challenges; promising concept rather than established therapy 2024, 2025 https://doi.org/10.3390/v16101616 ; https://doi.org/10.3390/v17050664 (branda2025humantlymphotropicvirus pages 23-25, wang2024currentstateof pages 1-2)

Table: This table summarizes key established and emerging treatment strategies for adult T-cell leukemia/lymphoma, including clinical setting, efficacy signals, and major safety limitations. It is useful for quickly comparing frontline, relapsed, transplant, and investigational approaches using only evidence retrieved in this run.

Key points: - AZT/IFN remains a widely used antiviral/immune-modulating regimen with pooled response estimates in a 2023 meta-analysis (OR 67%, CR 33%) and signals of greater benefit in indolent disease and in frontline combination use (shafiee2023zidovudineandinterferon pages 1-2, shafiee2023zidovudineandinterferon pages 4-6). - Mogamulizumab (anti-CCR4) shows clinically meaningful activity in relapsed aggressive ATL (phase II median OS 14.4 months; PFS 5.2 months) with rash as an immune-related AE correlated with improved outcomes (ishida2017mogamulizumabforrelapsed pages 1-2). Real-world results vary (e.g., ORR 36% and OS 4.0 months in one retrospective cohort) (sekine2017effectsofmogamulizumab pages 10-14). - Chemoimmunotherapy (mLSG15 + mogamulizumab) improved CR rates compared with chemotherapy alone, but with higher toxicity and opportunistic infections (wang2024currentstateof pages 12-14). - Allo-HSCT is emphasized as the only potentially curative approach in recent reviews and depends on eligibility and timing; pretransplant mogamulizumab exposure increases GVHD and mortality risk, motivating washout periods (wang2024currentstateof pages 34-35, wang2024currentstateof pages 12-14).

12.2 Suggested MAXO terms (examples)

(IDs should be verified against MAXO.) - Antiviral therapy (AZT/IFN) (shafiee2023zidovudineandinterferon pages 1-2) - Combination chemotherapy (iordan2024clinicalfeaturesand pages 1-2) - Monoclonal antibody therapy (mogamulizumab) (ishida2017mogamulizumabforrelapsed pages 1-2) - Hematopoietic stem cell transplantation (allo-HSCT) (nakahata2023understandingtheimmunopathology pages 2-3) - CAR T-cell therapy (investigational) (epsteinpeterson2025newtreatmentsfor pages 15-15)

13. Prevention

ATLL prevention is largely primary prevention of HTLV-1 acquisition, because disease typically follows long-term infection.

Breastfeeding modification: Early cessation of breastfeeding reduces transmission risk “from 14% to 4%” (o’donnell2023integratedmolecularand pages 2-3). A US-focused review states refraining from breastfeeding in HTLV-1-positive mothers can prevent 87% of early-life infections; short-term breastfeeding up to 3 months is proposed when formula is infeasible (altieri2025htlv1andatll pages 12-14).

Blood donor screening: Blood-donor screening is linked to a “significant reduction in transmission through blood transfusions” (branda2025humantlymphotropicvirus pages 10-12).

Organ donor screening: Receiving an organ from an HTLV-1-positive donor was described as having “100% risk of infection” (altieri2025htlv1andatll pages 4-5).

Sexual and injection-related transmission prevention: Safe-sex practices, partner testing/counseling, and harm-reduction needle exchange programs are recommended in public-health frameworks (altieri2025htlv1andatll pages 12-14).

14. Other Species / Natural Disease

This run retrieved animal-model discussions relevant to experimental systems (see Model Organisms) but did not retrieve evidence of naturally occurring ATLL in non-human species.

15. Model Organisms

A 2024 HTLV-1 therapeutics review summarizes multiple model systems: - Transgenic mice: Tax transgenic mice established Tax as an oncoprotein but often developed mesenchymal tumors rather than frank ATL-like disease; HBZ transgenic expression in CD4+ T cells induced leukemia/lymphoma after a long latency, aligning with HBZ constitutive expression in ATL (wang2024currentstateof pages 9-11, wang2024currentstateof pages 8-9). - Xenografts / patient-derived xenografts: NOD/SCID and NOG mice engrafted with ATL cells better recapitulate disease; the MET-1 NOD/SCID model demonstrated tumor inhibition and prolonged survival with daclizumab + depsipeptide (HDAC inhibitor) (wang2024currentstateof pages 8-9). - Humanized mice: Models (e.g., huNSG formats) allow HTLV-1 infection with rising proviral load, clonal CD25+CD4+ expansion, and ATL-like pathology; limitations include incomplete recapitulation of long-term persistence and immune context (wang2024currentstateof pages 9-11).

Limitations of this evidence run

  • Formal ICD/MeSH/MONDO/Orphanet/OMIM identifiers were not retrieved from the accessed full texts.
  • Several key sources are 2025 (still recent and authoritative), because some 2023 guideline documents were published later; core mechanistic sources prioritized include 2023–2024 reviews.
  • Some treatment modalities (lenalidomide, brentuximab, valemetostat) are mentioned but lacked extractable trial efficacy numbers in retrieved excerpts.

Key references (URLs/DOIs and publication dates)

  • O’Donnell et al. Lancet Haematology (2023-07). https://doi.org/10.1016/S2352-3026(23)00087-X (o’donnell2023integratedmolecularand pages 3-4)
  • Nakahata et al. Biomolecules (2023-10). https://doi.org/10.3390/biom13101543 (nakahata2023understandingtheimmunopathology pages 1-2)
  • Wang et al. Viruses (2024-10). https://doi.org/10.3390/v16101616 (wang2024currentstateof pages 1-2)
  • Shafiee et al. Virology Journal (2023-06). https://doi.org/10.1186/s12985-023-02077-0 (shafiee2023zidovudineandinterferon pages 1-2)
  • Ishida et al. Cancer Science (2017-08). https://doi.org/10.1111/cas.13343 (ishida2017mogamulizumabforrelapsed pages 1-2)
  • Iordan et al. Medicina (2024-05). https://doi.org/10.3390/medicina60060872 (iordan2024clinicalfeaturesand pages 1-2)
  • Nosaka & Fukushima International Journal of Hematology (2025-06; “JSH practical guidelines 2023”). https://doi.org/10.1007/s12185-025-04011-2 (nosaka2025jshpracticalguidelines pages 1-3)

References

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