🏷

Classifications

Harrison's Chapter

Mechanistic Nosology

ICD-O Morphology

🔗

Mappings

MONDO

MONDO:0011908 juvenile myelomonocytic leukemia

Primary MONDO disease identifier for canonical JMML.

◆

Subtypes

5

PTPN11-mutated JMML

JMML in nonsyndromic children with heterozygous somatic gain-of-function PTPN11 mutations encoding SHP2.

Show evidence (1 reference)

PMID:30670449 SUPPORT Human Clinical

"Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children"

Defines the PTPN11-mutated JMML subtype as a somatic molecular-driver subtype occurring in nonsyndromic children.

NRAS-mutated JMML

JMML with heterozygous somatic NRAS gain-of-function mutation. Some cases can show comparatively indolent behavior or spontaneous clinical remission.

Show evidence (2 references)

PMID:30670449 SUPPORT Human Clinical

"Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children"

Defines NRAS-mutated JMML as one of the canonical somatic molecular-driver subtypes.

PMID:39123476 PARTIAL Human Clinical

"Spontaneous clinical remission occurred in one patient with somatic NRAS mutation"

Supports that at least a subset of somatic NRAS-mutated JMML can show spontaneous clinical remission.

KRAS-mutated JMML

JMML with heterozygous somatic KRAS gain-of-function mutation in a nonsyndromic child.

Show evidence (1 reference)

PMID:30670449 SUPPORT Human Clinical

"Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children"

Defines KRAS-mutated JMML as one of the canonical somatic molecular-driver subtypes.

NF1-associated JMML

JMML arising in neurofibromatosis type 1 with acquired biallelic NF1 inactivation in hematopoietic cells.

Show evidence (1 reference)

PMID:30670449 SUPPORT Human Clinical

"whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells"

Defines NF1-associated JMML as a canonical predisposition-associated subtype with germline Ras disease plus hematopoietic second-hit inactivation.

CBL-associated JMML

JMML arising in children with CBL syndrome and acquired biallelic CBL inactivation in hematopoietic cells. This subtype can show spontaneous regression but still carries late vascular and relapse-associated risk.

Show evidence (2 references)

PMID:30670449 SUPPORT Human Clinical

"whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells"

Defines CBL-associated JMML as a canonical predisposition-associated subtype with germline Ras disease plus hematopoietic second-hit inactivation.

PMID:32460983 PARTIAL Human Clinical

"While spontaneous regression has been seen in germline PTPN11 and CBL mutant JMML, in most patients, allogeneic stem cell transplant is the only curative modality."

Supports the clinically distinctive natural history of CBL-associated JMML, including the possibility of spontaneous regression.

⚙

Pathophysiology

5

Ras Pathway Driver Lesion

Canonical JMML is initiated by germline or somatic lesions in one of five dominant Ras-pathway genes: PTPN11, NRAS, KRAS, NF1, or CBL. These lesions establish the core disease program and define the major molecular-driver subtype axis used in this entry.

hematopoietic stem cell link

Ras protein signal transduction link ↑ INCREASED

Downstream

RAS/MAPK Pathway Hyperactivation Canonical Ras-pathway lesions maintain constitutive downstream signaling

Show evidence (2 references)

PMID:30670449 SUPPORT Human Clinical

"About 90% of patients harbor molecular alterations in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically distinct subtypes."

Supports that the dominant disease-defining lesions in JMML lie in the five canonical Ras-pathway genes.

PMID:26457647 SUPPORT Human Clinical

"Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients"

Independent genomic cohort confirms the same five canonical Ras-pathway driver genes across the JMML disease unit.

RAS/MAPK Pathway Hyperactivation

JMML signaling output is characterized by constitutive Ras and ERK pathway activation. This is the central biochemical consequence of the canonical driver lesions and creates the mechanistic rationale for MEK inhibition.

Ras protein signal transduction link ↑ INCREASED MAPK cascade link ↑ INCREASED

Downstream

GM-CSF Hypersensitive Signaling Constitutive Ras signaling lowers the threshold for myeloid cytokine signaling

Show evidence (2 references)

PMID:30670449 SUPPORT Human Clinical

"JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway."

Supports constitutive Ras signaling as the core mechanistic feature of JMML.

PMID:29884903 SUPPORT In Vitro

"We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and CBL iPSC-derived myeloid cells."

Patient-derived iPSC modeling confirms constitutive Ras/MAPK pathway activation across canonical JMML genetic subtypes.

GM-CSF Hypersensitive Signaling

JMML progenitors show exaggerated signaling and colony growth responses to low concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF). This functional phenotype is linked to enhanced STAT5 and ERK activation and is one of the classic hallmarks of the disease.

common myeloid progenitor link

cytokine-mediated signaling pathway link ↑ INCREASED

Downstream

Myelomonocytic Progenitor Expansion Hypersensitive cytokine signaling drives abnormal myeloid colony growth

Show evidence (2 references)

PMID:22195407 SUPPORT Human Clinical

"The hallmark of JMML is hypersensitivity of marrow progenitors to granulocyte-monocyte colony stimulating factor (GM-CSF) in vitro."

Establishes GM-CSF hypersensitivity as a defining disease-level functional feature of JMML marrow progenitors.

PMID:23620576 SUPPORT In Vitro

"In vitro differentiation of JMML iPSCs produced myeloid cells with increased proliferative capacity, constitutive activation of granulocyte macrophage colony-stimulating factor (GM-CSF), and enhanced STAT5/ERK phosphorylation, similar to primary JMML cells from patients."

Links GM-CSF hypersensitivity to enhanced STAT5/ERK signaling in a patient-derived in vitro JMML model.

Myelomonocytic Progenitor Expansion

Hyperactive Ras and GM-CSF signaling expands the myeloid and monocytic compartments, producing peripheral leukocytosis with absolute monocytosis, cytopenias, and hypercellular marrow with myelomonocytic proliferation.

common myeloid progenitor link monocyte link

cell population proliferation link ↑ INCREASED

bone marrow link

Downstream

Organomegaly and Marrow Failure Features Expanded leukemic myelomonocytic cells drive splenic enlargement and cytopenias

Show evidence (2 references)

PMID:22195407 SUPPORT Human Clinical

"The peripheral blood usually show leukocytosis, absolute monocytosis, often with dysplastic features, anemia, and thrombocytopenia."

Supports the direct clinical consequences of expanded myelomonocytic proliferation in blood.

PMID:22195407 SUPPORT Human Clinical

"While the bone marrow findings are less specific, hypercellularity due to myelomonocytic proliferation, mild dysplasia, and a reduced number of megakaryocytes are usually present."

Supports marrow hypercellularity from myelomonocytic proliferation as the tissue-level correlate of the expanded progenitor compartment.

DNA Hypermethylation

A subset of JMML acquires a high-methylation epigenetic state associated with aggressive biology, increased relapse risk, and poor survival. This is best treated as a high-risk mechanism layer within JMML rather than a separate disease page.

DNA hypermethylation link ↑ INCREASED

Show evidence (1 reference)

PMID:21406719 SUPPORT Human Clinical

"In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome."

Supports a distinct epigenetically aggressive JMML state associated with poor clinical outcome.

✶

Histopathology

3

JMML Morphology

Disease-adjacent cancer grounding for JMML as a pediatric myelodysplastic/myeloproliferative leukemia entity.

Show evidence (1 reference)

PMID:32460983 SUPPORT Human Clinical

"Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained peripheral blood monocytosis, aggressive features, and poor outcomes."

Supports JMML as a distinct pediatric myelodysplastic/myeloproliferative leukemia entity and provides the disease-adjacent NCIT cancer grounding.

Bone Marrow Hypercellularity

Marrow is typically hypercellular because of expanded granulocytic and monocytic progenitors.

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"While the bone marrow findings are less specific, hypercellularity due to myelomonocytic proliferation, mild dysplasia, and a reduced number of megakaryocytes are usually present."

Directly supports bone marrow hypercellularity as a common histopathologic feature of JMML.

Myelodysplasia

Mild dysplasia accompanies the hyperproliferative marrow phenotype and contributes to the MDS/MPN overlap classification.

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"While the bone marrow findings are less specific, hypercellularity due to myelomonocytic proliferation, mild dysplasia, and a reduced number of megakaryocytes are usually present."

The pathology review explicitly notes mild dysplasia in JMML marrow.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Target 'Organomegaly and Marrow Failure Features' (from 'Myelomonocytic Progenitor Expansion') not found in named elements

●

Phenotypes

6

Blood 3

Leukocytosis Increased total leukocyte count (HP:0001974)

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"The peripheral blood usually show leukocytosis, absolute monocytosis, often with dysplastic features, anemia, and thrombocytopenia."

Supports leukocytosis as a characteristic peripheral blood feature of JMML.

Anemia Anemia (HP:0001903)

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"The peripheral blood usually show leukocytosis, absolute monocytosis, often with dysplastic features, anemia, and thrombocytopenia."

Supports anemia as part of the typical JMML blood phenotype.

Thrombocytopenia Thrombocytopenia (HP:0001873)

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"The peripheral blood usually show leukocytosis, absolute monocytosis, often with dysplastic features, anemia, and thrombocytopenia."

Supports thrombocytopenia as a characteristic blood-count abnormality in JMML.

Cardiovascular 1

Splenomegaly Splenomegaly (HP:0001744)

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"Children with JMML typically present with marked splenomegaly and hepatomegaly and varying degrees of lymphadenopathy, pallor, and skin rash."

Supports marked splenomegaly as a typical presenting feature of JMML.

Digestive 1

Hepatomegaly Hepatomegaly (HP:0002240)

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"Children with JMML typically present with marked splenomegaly and hepatomegaly and varying degrees of lymphadenopathy, pallor, and skin rash."

Supports hepatomegaly as a common organ-infiltration phenotype in JMML.

Other 1

Monocytosis Increased total monocyte count (HP:0012311)

Show evidence (1 reference)

PMID:32460983 SUPPORT Human Clinical

"Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained peripheral blood monocytosis, aggressive features, and poor outcomes."

Supports sustained peripheral blood monocytosis as a defining clinical feature of JMML.

🧬

Genetic Associations

7

PTPN11 (Somatic activating mutation)

NRAS (Somatic activating mutation)

KRAS (Somatic activating mutation)

NF1 (Germline predisposition with acquired biallelic inactivation)

CBL (Germline predisposition with acquired biallelic inactivation)

SETBP1 (Cooperating somatic mutation)

ASXL1 (Cooperating somatic mutation)

💊

Treatments

3

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic hematopoietic stem cell transplantation Ontology label: hematopoietic stem cell transplantation MAXO:0000747

Allogeneic hematopoietic stem cell transplantation remains the only curative therapy for most children with canonical JMML, although relapse and regimen-related toxicity remain major limitations.

Mechanism Target:

RESTORES Myelomonocytic Progenitor Expansion — Replaces the diseased hematopoietic compartment with donor hematopoiesis, restoring normal myeloid development rather than directly correcting Ras signaling inside the leukemic clone.

Show evidence (1 reference)

PMID:25435114 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplant is the only curative option for children with JMML, and it is fraught with frequent relapse and significant toxicity."

Supports allogeneic transplantation as the only established curative therapy for canonical JMML.

Show evidence (1 reference)

PMID:25435114 SUPPORT Human Clinical

"Allogeneic hematopoietic stem cell transplant is the only curative option for children with JMML, and it is fraught with frequent relapse and significant toxicity."

Supports allogeneic transplantation as the standard curative treatment for JMML.

Azacitidine

Action: pharmacotherapy MAXO:0000058

Agent: azacitidine ↗

Hypomethylating therapy used before transplantation to control disease burden and improve clinical status in newly diagnosed JMML. It is particularly useful as bridge therapy while definitive transplant is being arranged.

Mechanism Target:

INHIBITS DNA Hypermethylation — Azacitidine is used as a hypomethylating bridge therapy in JMML and is most mechanistically aligned with the aggressive hypermethylated risk state.

Show evidence (1 reference)

PMID:34297046 SUPPORT Human Clinical

"In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML."

Supports azacitidine as an active pre-transplant therapeutic option in JMML.

Show evidence (1 reference)

PMID:34297046 SUPPORT Human Clinical

"these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT."

Trial data support azacitidine as a clinically beneficial bridge to HSCT.

Trametinib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: trametinib ↗

MEK inhibitor with demonstrated activity in relapsed or refractory JMML and growing use as a bridge to HSCT or prolonged disease-control therapy in selected patients.

Mechanism Target:

INHIBITS RAS/MAPK Pathway Hyperactivation — Trametinib directly inhibits MEK1/2 downstream of Ras, making it the most direct targeted therapy for the canonical hyperactive MAPK program in JMML.

Show evidence (1 reference)

PMID:38867349 SUPPORT Human Clinical

"This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML."

Supports the mechanistic alignment of trametinib with MEK-pathway inhibition in JMML.

Show evidence (1 reference)

PMID:38867349 SUPPORT Human Clinical

"This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%."

Supports clinical activity of trametinib in relapsed or refractory JMML.

🔬

Biochemical Markers

3

Fetal Hemoglobin

Show evidence (1 reference)

PMID:30670449 SUPPORT Human Clinical

"The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count."

Supports elevated fetal hemoglobin as a clinically relevant JMML laboratory and risk-stratification feature.

GM-CSF Hypersensitivity Assay

Show evidence (1 reference)

PMID:22195407 SUPPORT Human Clinical

"The hallmark of JMML is hypersensitivity of marrow progenitors to granulocyte-monocyte colony stimulating factor (GM-CSF) in vitro."

Supports GM-CSF hypersensitivity as the classic functional biomarker assay for JMML.

DNA Methylation Signature

Show evidence (1 reference)

PMID:21406719 SUPPORT Human Clinical

"In conclusion, our data suggest that a high-methylation phenotype characterizes an aggressive biologic variant of JMML and is an important molecular predictor of outcome."

Supports DNA methylation profiling as a clinically informative biomarker layer in JMML.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Juvenile Myelomonocytic Leukemia:

Noonan syndrome-associated myeloproliferative disorder

Overlapping Features JMML-like myeloproliferation arising in the context of germline RASopathy mutations, especially germline PTPN11-associated Noonan syndrome. This entity often behaves differently from canonical JMML and frequently does not require transplantation.

Distinguishing Features

Germline Noonan syndrome or RASopathy context rather than canonical JMML alone
Spontaneous clinical resolution can occur without chemotherapy or transplantation
Excluded from the JMML subtype axis in this entry because the causal program and management can differ

Show evidence (1 reference)

PMID:39123476 SUPPORT Human Clinical

"Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention."

Supports modeling NS-MPD as a distinct clinical context rather than as a routine JMML subtype facet.

{ }

Source YAML

click to show

name: Juvenile Myelomonocytic Leukemia
creation_date: '2026-04-13T05:34:22Z'
updated_date: '2026-04-22T20:13:21Z'
description: >-
  Juvenile myelomonocytic leukemia (JMML) is a rare pediatric
  myelodysplastic/myeloproliferative neoplasm driven in most cases by Ras-pathway
  lesions involving PTPN11, NRAS, KRAS, NF1, or CBL. It presents with sustained
  peripheral blood monocytosis, splenomegaly, hepatomegaly, cytopenias, and
  granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity.
  Clinical behavior ranges from spontaneous resolution in a minority of biologically
  favorable cases to aggressive disease with post-transplant relapse and acute
  myeloid leukemia transformation. This entry models canonical JMML as the
  disease-level mechanism graph; Noonan syndrome-associated myeloproliferative
  disorder is handled as a differential context rather than a JMML subtype because
  its natural history and management frequently differ.
synonyms:
- JMML
- juvenile chronic myelomonocytic leukemia
categories:
- Hematologic Malignancy
- Pediatric Leukemia
- Myelodysplastic/Myeloproliferative Neoplasm
- RAS Pathway-Driven Cancer
parents:
- myelodysplastic/myeloproliferative neoplasm
has_subtypes:
- name: PTPN11-mutated
  display_name: PTPN11-mutated JMML
  classification: molecular_driver
  description: >-
    JMML in nonsyndromic children with heterozygous somatic gain-of-function
    PTPN11 mutations encoding SHP2.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are
      characterized by heterozygous somatic gain-of-function mutations in
      nonsyndromic children
    explanation: >-
      Defines the PTPN11-mutated JMML subtype as a somatic molecular-driver
      subtype occurring in nonsyndromic children.
- name: NRAS-mutated
  display_name: NRAS-mutated JMML
  classification: molecular_driver
  description: >-
    JMML with heterozygous somatic NRAS gain-of-function mutation. Some cases can
    show comparatively indolent behavior or spontaneous clinical remission.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are
      characterized by heterozygous somatic gain-of-function mutations in
      nonsyndromic children
    explanation: >-
      Defines NRAS-mutated JMML as one of the canonical somatic molecular-driver
      subtypes.
  - reference: PMID:39123476
    reference_title: "Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spontaneous clinical remission occurred in one patient with somatic NRAS
      mutation
    explanation: >-
      Supports that at least a subset of somatic NRAS-mutated JMML can show
      spontaneous clinical remission.
- name: KRAS-mutated
  display_name: KRAS-mutated JMML
  classification: molecular_driver
  description: >-
    JMML with heterozygous somatic KRAS gain-of-function mutation in a
    nonsyndromic child.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are
      characterized by heterozygous somatic gain-of-function mutations in
      nonsyndromic children
    explanation: >-
      Defines KRAS-mutated JMML as one of the canonical somatic molecular-driver
      subtypes.
- name: NF1-associated
  display_name: NF1-associated JMML
  classification: molecular_driver
  description: >-
    JMML arising in neurofibromatosis type 1 with acquired biallelic NF1
    inactivation in hematopoietic cells.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children
      with CBL syndrome, are defined by germline Ras disease and acquired
      biallelic inactivation of the respective genes in hematopoietic cells
    explanation: >-
      Defines NF1-associated JMML as a canonical predisposition-associated subtype
      with germline Ras disease plus hematopoietic second-hit inactivation.
- name: CBL-associated
  display_name: CBL-associated JMML
  classification: molecular_driver
  description: >-
    JMML arising in children with CBL syndrome and acquired biallelic CBL
    inactivation in hematopoietic cells. This subtype can show spontaneous
    regression but still carries late vascular and relapse-associated risk.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children
      with CBL syndrome, are defined by germline Ras disease and acquired
      biallelic inactivation of the respective genes in hematopoietic cells
    explanation: >-
      Defines CBL-associated JMML as a canonical predisposition-associated subtype
      with germline Ras disease plus hematopoietic second-hit inactivation.
  - reference: PMID:32460983
    reference_title: "Juvenile myelomonocytic leukemia - A bona fide RASopathy syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While spontaneous regression has been seen in germline PTPN11 and CBL
      mutant JMML, in most patients, allogeneic stem cell transplant is the only
      curative modality.
    explanation: >-
      Supports the clinically distinctive natural history of CBL-associated JMML,
      including the possibility of spontaneous regression.
disease_term:
  preferred_term: juvenile myelomonocytic leukemia
  term:
    id: MONDO:0011908
    label: juvenile myelomonocytic leukemia
pathophysiology:
- name: Ras Pathway Driver Lesion
  description: >-
    Canonical JMML is initiated by germline or somatic lesions in one of five
    dominant Ras-pathway genes: PTPN11, NRAS, KRAS, NF1, or CBL. These lesions
    establish the core disease program and define the major molecular-driver
    subtype axis used in this entry.
  subtypes:
  - PTPN11-mutated
  - NRAS-mutated
  - KRAS-mutated
  - NF1-associated
  - CBL-associated
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  downstream:
  - target: RAS/MAPK Pathway Hyperactivation
    description: Canonical Ras-pathway lesions maintain constitutive downstream signaling
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About 90% of patients harbor molecular alterations in 1 of 5 genes
      (PTPN11, NRAS, KRAS, NF1, or CBL), which define genetically and clinically
      distinct subtypes.
    explanation: >-
      Supports that the dominant disease-defining lesions in JMML lie in the
      five canonical Ras-pathway genes.
  - reference: PMID:26457647
    reference_title: "The genomic landscape of juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients
    explanation: >-
      Independent genomic cohort confirms the same five canonical Ras-pathway
      driver genes across the JMML disease unit.
- name: RAS/MAPK Pathway Hyperactivation
  description: >-
    JMML signaling output is characterized by constitutive Ras and ERK pathway
    activation. This is the central biochemical consequence of the canonical
    driver lesions and creates the mechanistic rationale for MEK inhibition.
  biological_processes:
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  downstream:
  - target: GM-CSF Hypersensitive Signaling
    description: Constitutive Ras signaling lowers the threshold for myeloid cytokine signaling
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      JMML pathobiology is characterized by constitutive activation of the Ras
      signal transduction pathway.
    explanation: >-
      Supports constitutive Ras signaling as the core mechanistic feature of JMML.
  - reference: PMID:29884903
    reference_title: "Mutation-specific signaling profiles and kinase inhibitor sensitivities of juvenile myelomonocytic leukemia revealed by induced pluripotent stem cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and
      CBL iPSC-derived myeloid cells.
    explanation: >-
      Patient-derived iPSC modeling confirms constitutive Ras/MAPK pathway
      activation across canonical JMML genetic subtypes.
- name: GM-CSF Hypersensitive Signaling
  description: >-
    JMML progenitors show exaggerated signaling and colony growth responses to low
    concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF).
    This functional phenotype is linked to enhanced STAT5 and ERK activation and
    is one of the classic hallmarks of the disease.
  cell_types:
  - preferred_term: common myeloid progenitor
    term:
      id: CL:0000049
      label: common myeloid progenitor
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
  downstream:
  - target: Myelomonocytic Progenitor Expansion
    description: Hypersensitive cytokine signaling drives abnormal myeloid colony growth
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark of JMML is hypersensitivity of marrow progenitors to
      granulocyte-monocyte colony stimulating factor (GM-CSF) in vitro.
    explanation: >-
      Establishes GM-CSF hypersensitivity as a defining disease-level functional
      feature of JMML marrow progenitors.
  - reference: PMID:23620576
    reference_title: "Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro differentiation of JMML iPSCs produced myeloid cells with
      increased proliferative capacity, constitutive activation of granulocyte
      macrophage colony-stimulating factor (GM-CSF), and enhanced STAT5/ERK
      phosphorylation, similar to primary JMML cells from patients.
    explanation: >-
      Links GM-CSF hypersensitivity to enhanced STAT5/ERK signaling in a
      patient-derived in vitro JMML model.
- name: Myelomonocytic Progenitor Expansion
  description: >-
    Hyperactive Ras and GM-CSF signaling expands the myeloid and monocytic
    compartments, producing peripheral leukocytosis with absolute monocytosis,
    cytopenias, and hypercellular marrow with myelomonocytic proliferation.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  cell_types:
  - preferred_term: common myeloid progenitor
    term:
      id: CL:0000049
      label: common myeloid progenitor
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  downstream:
  - target: Organomegaly and Marrow Failure Features
    description: Expanded leukemic myelomonocytic cells drive splenic enlargement and cytopenias
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The peripheral blood usually show leukocytosis, absolute monocytosis,
      often with dysplastic features, anemia, and thrombocytopenia.
    explanation: >-
      Supports the direct clinical consequences of expanded myelomonocytic
      proliferation in blood.
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the bone marrow findings are less specific, hypercellularity due to
      myelomonocytic proliferation, mild dysplasia, and a reduced number of
      megakaryocytes are usually present.
    explanation: >-
      Supports marrow hypercellularity from myelomonocytic proliferation as the
      tissue-level correlate of the expanded progenitor compartment.
- name: DNA Hypermethylation
  description: >-
    A subset of JMML acquires a high-methylation epigenetic state associated with
    aggressive biology, increased relapse risk, and poor survival. This is best
    treated as a high-risk mechanism layer within JMML rather than a separate
    disease page.
  biological_processes:
  - preferred_term: DNA hypermethylation
    modifier: INCREASED
    term:
      id: GO:0044027
      label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence:
  - reference: PMID:21406719
    reference_title: "Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, our data suggest that a high-methylation phenotype
      characterizes an aggressive biologic variant of JMML and is an important
      molecular predictor of outcome.
    explanation: >-
      Supports a distinct epigenetically aggressive JMML state associated with
      poor clinical outcome.
histopathology:
- name: JMML Morphology
  finding_term:
    preferred_term: Juvenile Myelomonocytic Leukemia
    term:
      id: NCIT:C9233
      label: Juvenile Myelomonocytic Leukemia
  diagnostic: true
  description: >-
    Disease-adjacent cancer grounding for JMML as a pediatric
    myelodysplastic/myeloproliferative leukemia entity.
  evidence:
  - reference: PMID:32460983
    reference_title: "Juvenile myelomonocytic leukemia - A bona fide RASopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Juvenile myelomonocytic leukemia (JMML) is a pediatric
      myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained
      peripheral blood monocytosis, aggressive features, and poor outcomes.
    explanation: >-
      Supports JMML as a distinct pediatric myelodysplastic/myeloproliferative
      leukemia entity and provides the disease-adjacent NCIT cancer grounding.
- name: Bone Marrow Hypercellularity
  finding_term:
    preferred_term: myelomonocytic proliferation
    term:
      id: NCIT:C19955
      label: Myeloproliferation
  description: >-
    Marrow is typically hypercellular because of expanded granulocytic and
    monocytic progenitors.
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the bone marrow findings are less specific, hypercellularity due to
      myelomonocytic proliferation, mild dysplasia, and a reduced number of
      megakaryocytes are usually present.
    explanation: >-
      Directly supports bone marrow hypercellularity as a common histopathologic
      feature of JMML.
- name: Myelodysplasia
  finding_term:
    preferred_term: Myelodysplasia
    term:
      id: NCIT:C4086
      label: Dysplasia
  description: >-
    Mild dysplasia accompanies the hyperproliferative marrow phenotype and
    contributes to the MDS/MPN overlap classification.
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the bone marrow findings are less specific, hypercellularity due to
      myelomonocytic proliferation, mild dysplasia, and a reduced number of
      megakaryocytes are usually present.
    explanation: >-
      The pathology review explicitly notes mild dysplasia in JMML marrow.
phenotypes:
- category: Hematologic
  name: Monocytosis
  diagnostic: true
  description: >-
    Sustained absolute peripheral blood monocytosis is a defining hematologic
    feature of canonical JMML.
  phenotype_term:
    preferred_term: Monocytosis
    term:
      id: HP:0012311
      label: Increased total monocyte count
  evidence:
  - reference: PMID:32460983
    reference_title: "Juvenile myelomonocytic leukemia - A bona fide RASopathy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Juvenile myelomonocytic leukemia (JMML) is a pediatric
      myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained
      peripheral blood monocytosis, aggressive features, and poor outcomes.
    explanation: >-
      Supports sustained peripheral blood monocytosis as a defining clinical
      feature of JMML.
- category: Abdominal
  name: Splenomegaly
  description: >-
    Marked splenomegaly reflects extramedullary accumulation of JMML cells and is
    one of the most characteristic presenting findings.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with JMML typically present with marked splenomegaly and
      hepatomegaly and varying degrees of lymphadenopathy, pallor, and skin
      rash.
    explanation: >-
      Supports marked splenomegaly as a typical presenting feature of JMML.
- category: Abdominal
  name: Hepatomegaly
  description: >-
    Hepatic enlargement commonly accompanies splenic disease because JMML cells
    infiltrate reticuloendothelial tissues.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children with JMML typically present with marked splenomegaly and
      hepatomegaly and varying degrees of lymphadenopathy, pallor, and skin
      rash.
    explanation: >-
      Supports hepatomegaly as a common organ-infiltration phenotype in JMML.
- category: Hematologic
  name: Leukocytosis
  description: >-
    Total white blood cell count is often elevated because of expansion of the
    myeloid and monocytic compartments.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The peripheral blood usually show leukocytosis, absolute monocytosis,
      often with dysplastic features, anemia, and thrombocytopenia.
    explanation: >-
      Supports leukocytosis as a characteristic peripheral blood feature of JMML.
- category: Hematologic
  name: Anemia
  description: >-
    Anemia reflects marrow dysfunction and replacement by proliferating
    myelomonocytic cells.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The peripheral blood usually show leukocytosis, absolute monocytosis,
      often with dysplastic features, anemia, and thrombocytopenia.
    explanation: >-
      Supports anemia as part of the typical JMML blood phenotype.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Platelet count is often depressed at presentation and is also an important
    clinical risk marker.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The peripheral blood usually show leukocytosis, absolute monocytosis,
      often with dysplastic features, anemia, and thrombocytopenia.
    explanation: >-
      Supports thrombocytopenia as a characteristic blood-count abnormality in JMML.
biochemical:
- name: Fetal Hemoglobin
  notes: >-
    Elevated hemoglobin F is a classic laboratory abnormality in JMML and also
    contributes to risk stratification alongside age and platelet count.
  evidence:
  - reference: PMID:30670449
    reference_title: "Juvenile myelomonocytic leukemia: who's the driver at the wheel?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course of the disease varies widely and can in part be
      predicted by age, level of hemoglobin F, and platelet count.
    explanation: >-
      Supports elevated fetal hemoglobin as a clinically relevant JMML
      laboratory and risk-stratification feature.
- name: GM-CSF Hypersensitivity Assay
  notes: >-
    Functional hypersensitivity of marrow progenitors to low-dose GM-CSF remains
    a hallmark assay-level biomarker of canonical JMML biology.
  evidence:
  - reference: PMID:22195407
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hallmark of JMML is hypersensitivity of marrow progenitors to
      granulocyte-monocyte colony stimulating factor (GM-CSF) in vitro.
    explanation: >-
      Supports GM-CSF hypersensitivity as the classic functional biomarker assay
      for JMML.
- name: DNA Methylation Signature
  notes: >-
    Genome-wide methylation profiling refines risk stratification; a high-methylation
    state predicts aggressive disease and post-transplant relapse.
  evidence:
  - reference: PMID:21406719
    reference_title: "Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, our data suggest that a high-methylation phenotype
      characterizes an aggressive biologic variant of JMML and is an important
      molecular predictor of outcome.
    explanation: >-
      Supports DNA methylation profiling as a clinically informative biomarker
      layer in JMML.
genetic:
- name: PTPN11
  association: Somatic activating mutation
  subtype: PTPN11-mutated
  notes: >-
    Heterozygous somatic gain-of-function PTPN11 mutations are one of the
    canonical disease-defining Ras-pathway lesions in nonsyndromic JMML and are
    strongly associated with MAPK-pathway dependence.
- name: NRAS
  association: Somatic activating mutation
  subtype: NRAS-mutated
  notes: >-
    Somatic NRAS gain-of-function mutation defines a canonical JMML molecular
    subtype. Some NRAS-mutated cases can show spontaneous clinical remission.
- name: KRAS
  association: Somatic activating mutation
  subtype: KRAS-mutated
  notes: >-
    Somatic KRAS gain-of-function mutation defines a canonical JMML molecular
    subtype in nonsyndromic children.
- name: NF1
  association: Germline predisposition with acquired biallelic inactivation
  subtype: NF1-associated
  notes: >-
    NF1-associated JMML arises in the setting of neurofibromatosis type 1 with
    acquired biallelic NF1 loss in hematopoietic cells.
- name: CBL
  association: Germline predisposition with acquired biallelic inactivation
  subtype: CBL-associated
  notes: >-
    CBL-associated JMML occurs in children with CBL syndrome and acquired
    biallelic inactivation of CBL in hematopoietic cells.
- name: SETBP1
  association: Cooperating somatic mutation
  notes: >-
    Secondary SETBP1 mutations contribute to clonal progression and relapse risk
    rather than defining the primary JMML disease unit.
- name: ASXL1
  association: Cooperating somatic mutation
  notes: >-
    Secondary ASXL1 mutations mark epigenetically aggressive JMML biology and can
    co-occur with high-methylation disease states.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation remains the only curative
    therapy for most children with canonical JMML, although relapse and regimen-related
    toxicity remain major limitations.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_mechanisms:
  - target: Myelomonocytic Progenitor Expansion
    treatment_effect: RESTORES
    description: >-
      Replaces the diseased hematopoietic compartment with donor hematopoiesis,
      restoring normal myeloid development rather than directly correcting Ras
      signaling inside the leukemic clone.
    evidence:
    - reference: PMID:25435114
      reference_title: "Juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Allogeneic hematopoietic stem cell transplant is the only curative
        option for children with JMML, and it is fraught with frequent relapse
        and significant toxicity.
      explanation: >-
        Supports allogeneic transplantation as the only established curative
        therapy for canonical JMML.
  evidence:
  - reference: PMID:25435114
    reference_title: "Juvenile myelomonocytic leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic hematopoietic stem cell transplant is the only curative
      option for children with JMML, and it is fraught with frequent relapse
      and significant toxicity.
    explanation: >-
      Supports allogeneic transplantation as the standard curative treatment for JMML.
- name: Azacitidine
  description: >-
    Hypomethylating therapy used before transplantation to control disease burden
    and improve clinical status in newly diagnosed JMML. It is particularly
    useful as bridge therapy while definitive transplant is being arranged.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: azacitidine
      term:
        id: CHEBI:2038
        label: 5-azacytidine
  target_mechanisms:
  - target: DNA Hypermethylation
    treatment_effect: INHIBITS
    description: >-
      Azacitidine is used as a hypomethylating bridge therapy in JMML and is most
      mechanistically aligned with the aggressive hypermethylated risk state.
    evidence:
    - reference: PMID:34297046
      reference_title: "Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In conclusion, azacitidine monotherapy is a suitable option for children
        with newly diagnosed JMML.
      explanation: >-
        Supports azacitidine as an active pre-transplant therapeutic option in JMML.
  evidence:
  - reference: PMID:34297046
    reference_title: "Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these data demonstrate that azacitidine provides valuable clinical benefit
      to JMML patients prior to HSCT.
    explanation: >-
      Trial data support azacitidine as a clinically beneficial bridge to HSCT.
- name: Trametinib
  description: >-
    MEK inhibitor with demonstrated activity in relapsed or refractory JMML and
    growing use as a bridge to HSCT or prolonged disease-control therapy in
    selected patients.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: trametinib
      term:
        id: CHEBI:75998
        label: trametinib
  target_mechanisms:
  - target: RAS/MAPK Pathway Hyperactivation
    treatment_effect: INHIBITS
    description: >-
      Trametinib directly inhibits MEK1/2 downstream of Ras, making it the most
      direct targeted therapy for the canonical hyperactive MAPK program in JMML.
    evidence:
    - reference: PMID:38867349
      reference_title: "Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This phase II trial evaluated the safety and efficacy of trametinib, an
        oral MEK1/2 inhibitor, in patients with advanced JMML.
      explanation: >-
        Supports the mechanistic alignment of trametinib with MEK-pathway
        inhibition in JMML.
  evidence:
  - reference: PMID:38867349
    reference_title: "Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phase II trial evaluated the safety and efficacy of trametinib, an
      oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and
      children were enrolled, and the objective response rate was 50%.
    explanation: >-
      Supports clinical activity of trametinib in relapsed or refractory JMML.
differential_diagnoses:
- name: Noonan syndrome-associated myeloproliferative disorder
  description: >-
    JMML-like myeloproliferation arising in the context of germline RASopathy
    mutations, especially germline PTPN11-associated Noonan syndrome. This entity
    often behaves differently from canonical JMML and frequently does not require
    transplantation.
  distinguishing_features:
  - Germline Noonan syndrome or RASopathy context rather than canonical JMML alone
  - Spontaneous clinical resolution can occur without chemotherapy or transplantation
  - Excluded from the JMML subtype axis in this entry because the causal program and management can differ
  evidence:
  - reference: PMID:39123476
    reference_title: "Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with NS-MPD were excluded from treatment analysis as none required
      chemotherapeutic intervention.
    explanation: >-
      Supports modeling NS-MPD as a distinct clinical context rather than as a
      routine JMML subtype facet.
review_notes: >-
  Applied the cancer-curation guidance summarized from dismech issue 1198:
  canonical JMML is the single disease-level mechanism graph; driver-defined
  `has_subtypes` are flat facet annotations rather than separate pages; Noonan
  syndrome-associated MPD was kept out of `has_subtypes`; MONDO is primary for
  disease grounding; exact MONDO subtype terms were not identified for the five
  driver facets so unsupported subclass IDs were not forced into
  `subtype_term`; NCIT disease grounding is carried in the disease-adjacent
  cancer representation available in the current schema.
classifications:
  icdo_morphology:
    classification_value: Leukemia
    evidence:
    - reference: PMID:25435114
      reference_title: "Juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Juvenile myelomonocytic leukemia (JMML), a rare myeloid malignancy that
        occurs in young children
      explanation: >-
        Supports classification of JMML within the leukemia morphology axis.
  harrisons_chapter:
  - classification_value: cancer
    evidence:
    - reference: PMID:25435114
      reference_title: "Juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Juvenile myelomonocytic leukemia (JMML), a rare myeloid malignancy that
        occurs in young children
      explanation: >-
        Supports classification of JMML as a malignant cancer.
  - classification_value: hematologic malignancy
    evidence:
    - reference: PMID:25435114
      reference_title: "Juvenile myelomonocytic leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Juvenile myelomonocytic leukemia (JMML), a rare myeloid malignancy that
        occurs in young children
      explanation: >-
        Supports classification of JMML as a hematologic malignancy.
  mechanistic_category:
  - classification_value: RASopathy
    notes: >-
      JMML is a malignant pediatric myeloid neoplasm rather than a classical
      congenital RASopathy, but its core causal program is explicitly framed in
      the literature as Ras-pathway disease biology and even as a bona fide
      RASopathy syndrome.
    evidence:
    - reference: PMID:32460983
      reference_title: "Juvenile myelomonocytic leukemia - A bona fide RASopathy syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        JMML is a bona fide RASopathy, with additional somatic mutations,
        including in epigenetic regulators genes resulting in disease progression.
      explanation: >-
        Supports mechanistic classification of JMML within a RASopathy-centered
        nosologic framework.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011908
      label: juvenile myelomonocytic leukemia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for canonical JMML.

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Juvenile Myelomonocytic Leukemia: Manual Deep Research Summary

n/a 11 citations 2026-04-13T05:35:00Z

Juvenile Myelomonocytic Leukemia: Manual Deep Research Summary

Disease-level modeling decision

JMML should be modeled as one disease-level mechanism graph, not split into multiple pages for every ontology subclass or driver-defined variant. The strongest support for this comes from the 2019 review that states that about 90% of patients have lesions in one of five canonical Ras-pathway genes and that these define genetically and clinically distinct subtypes rather than wholly separate diseases (PMID:30670449). Following the #1198 cancer-curation guidance, the disease file therefore uses:

a single MONDO-first disease anchor for canonical JMML
flat has_subtypes facets for the molecular-driver axis (PTPN11-mutated, NRAS-mutated, KRAS-mutated, NF1-associated, CBL-associated)
no separate dismech page for those subtype facets

Noonan syndrome-associated myeloproliferative disorder (NS-MPD) was not folded into has_subtypes for the JMML entry. The real-world series in PMID:39123476 explicitly separated NS-MPD from JMML treatment analysis because none of the NS-MPD patients required chemotherapy, and spontaneous clinical remission was observed in that group. That supports treating NS-MPD as a related but distinct disease context or differential, not as an ordinary JMML subtype facet.

Ontology grounding choices

Primary disease term: MONDO:0011908 juvenile myelomonocytic leukemia
Disease-adjacent NCIT grounding: NCIT:C9233 Juvenile Myelomonocytic Leukemia
Key phenotype terms: monocytosis, splenomegaly, hepatomegaly, leukocytosis, anemia, thrombocytopenia
Key histopathology terms: bone marrow hypercellularity, myelodysplasia
Key mechanism terms: Ras protein signal transduction, MAPK cascade, cytokine-mediated signaling pathway, DNA methylation
Key treatment terms: hematopoietic stem cell transplantation, pharmacotherapy with azacitidine and trametinib as therapeutic agents

Because the current schema exposes MONDO-specific disease mappings but not dedicated NCIT disease mappings, NCIT grounding was carried in the disease-adjacent cancer representation rather than inventing a new schema pattern locally.

Core disease biology

Canonical defining lesion space

JMML is a pediatric myelodysplastic/myeloproliferative neoplasm overlap syndrome with sustained peripheral blood monocytosis and dominant Ras-pathway biology.

PMID:32460983 describes JMML as a pediatric MDS/MPN overlap syndrome with sustained peripheral blood monocytosis and poor outcomes.
PMID:30670449 states that JMML pathobiology is characterized by constitutive activation of Ras signal transduction and that about 90% of patients harbor lesions in PTPN11, NRAS, KRAS, NF1, or CBL.
PMID:26457647 found canonical lesions in NF1, NRAS, KRAS, PTPN11, or CBL in 85% of cases and showed that additional somatic alterations at diagnosis are strongly associated with outcome.

Atomic mechanism chain supported by the literature

Ras-pathway driver lesion
Canonical driver lesions involve PTPN11, NRAS, KRAS, NF1, or CBL (PMID:30670449, PMID:26457647).
RAS/MAPK pathway hyperactivation
Ras signaling is constitutively active in JMML (PMID:30670449).
Patient-derived iPSC models confirm constitutive Ras/MAPK signaling in PTPN11- and CBL-mutant JMML cells (PMID:29884903).
GM-CSF hypersensitive signaling
GM-CSF hypersensitivity is a disease hallmark in marrow progenitors (PMID:22195407).
iPSC-derived JMML cells show constitutive GM-CSF activation with enhanced STAT5/ERK phosphorylation (PMID:23620576).
Myelomonocytic progenitor expansion
This manifests as leukocytosis, absolute monocytosis, cytopenias, and marrow hypercellularity with myelomonocytic proliferation (PMID:22195407).
Epigenetically aggressive subset
High DNA methylation identifies an aggressive biologic JMML variant with worse survival and higher post-transplant relapse risk (PMID:21406719).

Phenotype and pathology summary

The most reusable phenotype/pathology extraction came from the pathology review PMID:22195407:

marked splenomegaly and hepatomegaly
leukocytosis
absolute monocytosis
anemia
thrombocytopenia
marrow hypercellularity due to myelomonocytic proliferation
mild dysplasia

PMID:29884903 additionally highlights elevated fetal hemoglobin and GM-CSF hypersensitivity as classic diagnostic/risk features.

Treatment evidence summary

Allogeneic hematopoietic stem cell transplantation

Transplant remains the only curative treatment for most canonical JMML cases.

PMID:25435114: allogeneic hematopoietic stem cell transplant is the only curative option, but relapse and toxicity remain substantial.
PMID:30670449: most children require allogeneic hematopoietic stem cell transplantation for long-term leukemia-free survival.

Azacitidine

Azacitidine has meaningful pre-transplant cytoreductive and clinical activity.

PMID:34297046: phase 2 AZA-JMML-001 showed 61% clinical partial remission after three cycles, with 82% leukemia-free survival after subsequent HSCT at median follow-up.
Response was strongest in intermediate- or low-methylation groups in that trial.

Trametinib

MEK inhibition has become credible salvage/bridging therapy for relapsed or refractory disease.

PMID:38867349: phase II Children's Oncology Group study reported an objective response rate of 50%.
Four refractory patients were bridged to HSCT after trametinib, and three additional patients remained on off-protocol trametinib without HSCT at report time.

Subtype-axis reasoning carried into the YAML

The curated subtype axis was limited to the canonical driver-defined JMML groups:

PTPN11-mutated
NRAS-mutated
KRAS-mutated
NF1-associated
CBL-associated

These were chosen because PMID:30670449 explicitly describes them as the five genetically and clinically distinct JMML subtypes. A separate methylation-risk axis was not added to has_subtypes; methylation state was instead modeled as an orthogonal pathobiologic/risk mechanism because it alters prognosis without necessarily defining a separate clinical disease page or distinct primary causal program.

Key references used

PMID:25435114
PMID:22195407
PMID:26457647
PMID:21406719
PMID:23620576
PMID:29884903
PMID:30670449
PMID:32460983
PMID:34297046
PMID:38867349
PMID:39123476

Juvenile Myelomonocytic Leukemia

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Juvenile Myelomonocytic Leukemia: Manual Deep Research Summary

Disease-level modeling decision

Ontology grounding choices

Core disease biology

Canonical defining lesion space

Atomic mechanism chain supported by the literature

Phenotype and pathology summary

Treatment evidence summary

Allogeneic hematopoietic stem cell transplantation

Azacitidine

Trametinib

Subtype-axis reasoning carried into the YAML

Key references used