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Mappings

MONDO

MONDO:0100280 Waldenstrom macroglobulinemia

Primary MONDO disease identifier for this Waldenstrom macroglobulinemia entry.

📘

Definitions

1

Pathologic definition of Waldenstrom macroglobulinemia

Waldenstrom macroglobulinemia is a distinct clinicopathologic entity defined by bone marrow infiltration by lymphoplasmacytic lymphoma together with an IgM monoclonal gammopathy.

CASE_DEFINITION General clinicopathologic definition for disease-level curation

Show evidence (1 reference)

PMID:12720118 SUPPORT Other

"WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy."

This consensus definition anchors WM as a disease entity defined by marrow lymphoplasmacytic infiltration together with IgM paraproteinemia.

◆

Subtypes

4

clinical course

Asymptomatic Waldenstrom Macroglobulinemia

Asymptomatic WM is managed with observation rather than immediate therapy unless there is critically elevated IgM or compromised hematopoietic function.

Show evidence (1 reference)

PMID:37099027 SUPPORT Other

"The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function."

This consensus update supports asymptomatic WM as a clinically meaningful disease-course subtype defined by deferred treatment.

Symptomatic Waldenstrom Macroglobulinemia

Symptomatic WM is the treatment-requiring clinical subset distinguished from asymptomatic WM and precursor IgM-related states.

Show evidence (1 reference)

PMID:12720118 SUPPORT Other

"Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed."

This consensus definition supports symptomatic WM as a clinically distinct treatment-triggering subtype axis within the same disease entry.

molecular

MYD88-mutant Waldenstrom Macroglobulinemia

MYD88 hgnc:7562

The dominant molecular subset of WM carries MYD88 L265P, an early oncogenic lesion that organizes the baseline disease program.

Show evidence (1 reference)

PMID:24224040 SUPPORT Human Clinical

"These results suggest that the L265P mutation is involved in the majority of Waldenström's macroglobulinemia."

This supports a MYD88-mutant molecular subset that belongs inside the same disease page rather than as a separate dismech entry.

CXCR4-mutated Waldenstrom Macroglobulinemia

CXCR4 hgnc:2561

A treatment-relevant molecular subset of WM acquires subclonal WHIM-like CXCR4 mutations layered onto the core disease program.

Show evidence (1 reference)

PMID:26659815 SUPPORT Human Clinical

"The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis."

This supports CXCR4-mutated WM as a molecular facet subtype nested within the broader Waldenstrom disease graph.

?

Discussions and Knowledge Gaps

1

Does a WNK2 isoform that carries the recurrent exon 27-28 skip and lacks the kinase domain (it starts from an internal transcription start site), and that WM tumor cells express at high levels, drive ERK1/2 and NF-κB signaling in Waldenström macroglobulinemia, and is that axis separable from MYD88 itself?

KNOWLEDGE GAP OPEN wm_wnk2_kd_lacking_isoform_signaling

Attached to

pathophysiology#MYD88 L265P Founder Mutation

The entry's pathophysiology places MYD88 L265P upstream of the malignant clone but does not carry the WNK2 isoform story. Guerrera et al. (PMID:42420257) report that novel cancer-specific WNK2 isoforms are highly expressed by WM tumor cells, that the kinase-domain-lacking isoform WNK2/S-NK1 is the most expressed of the kinase-domain-lacking isoforms in WM, and that it activates ERK1/2 and NF-κB, unlike the canonical full-length kinase, which inhibits ERK1/2 in a kinase-dependent manner. The same study reports a MYD88-independent route to WNK2 dysregulation, likely linked to aberrant methylation: MYD88 L265P overexpression in OCI-LY7 and Ramos did not raise WNK2. These are findings from tumor cells and cell-line work reported in one study. What is missing is how the kinase-domain-lacking isoform signals, what drives its splicing in WM cells, and whether this axis can be targeted separately from MYD88 inhibition, given that no WNK2-selective inhibitor currently exists.

Proposed experiments

Isoform-specific rescue in MYD88-mutant WM cells

wm_wnk2_s_nk1_isoform_rescue

Express the kinase-domain-lacking WNK2 isoform in a MYD88 wild-type background and in MYD88 L265P cells with isoform-specific knockdown, then read ERK1/2 and NF-κB activity. This separates the isoform's effect from MYD88-driven signaling.

The source reports that the S-K and S-NK exon 27-28 skipping families are also upregulated in cholangiocarcinoma, and that S-NK transcripts are present in normal colon, so these isoforms are not WM-specific. The functional data come from lentiviral transduction of WM cell lines.

Show evidence (5 references)

PMID:42420257 SUPPORT PRIMARY RESULT In Vitro

"Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling."

Lentiviral overexpression of the kinase-domain-lacking isoform in WM cell lines activated ERK1/2 and NF-κB signaling.

PMID:42420257 SUPPORT BACKGROUND In Vitro

"WNK2 negatively regulates ERK1/2 activation in a kinase-dependent manner through RHOA/RAC1 modulation of PAK1"

Prior cell work the paper cites for the inhibitory role of the canonical kinase-domain isoform on ERK1/2.

PMID:42420257 SUPPORT PRIMARY RESULT Human Clinical

"Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM."

Patient-derived expression profiling across 264 untreated WM cases shows WNK2 dysregulation from early disease.

+ 2 more references

⚙

Pathophysiology

6

Bone Marrow Lymphoplasmacytic Infiltration

The disease-defining tissue state is infiltration of the bone marrow by a clonal lymphoplasmacytic population spanning mature B-cell, plasmacytoid, and plasma-cell differentiation states.

B cell CL:0000236 plasma cell CL:0000786

cell population proliferation GO:0008283 ↑ INCREASED

bone marrow UBERON:0002371

Downstream

Monoclonal IgM Secretion The marrow lymphoplasmacytic clone gives rise to the circulating IgM paraprotein.

Show evidence (2 references)

PMID:12720118 SUPPORT Other

"WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy."

The consensus definition identifies marrow infiltration as a primary clinicopathologic feature of WM.

PMID:11718214 SUPPORT Other

"Lymphoplasmacytic-lymphoplasmacytoid lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) or immunocytoma (IMC) consists of diffuse proliferation of small mature B lymphocytes, plasmacytoid lymphocytes, and plasma-cells."

This abstract specifies the marrow-infiltrating tumor-cell composition that underlies the lymphoplasmacytic clone in WM.

Monoclonal IgM Secretion

The clonal lymphoplasmacytic population produces a monoclonal IgM paraprotein that accumulates in the circulation and mediates important downstream complications.

IgM plasma cell CL:0000986

immunoglobulin production GO:0002377 ↑ INCREASED

blood serum UBERON:0001977

Downstream

Serum Hyperviscosity Heavy circulating IgM burden increases serum viscosity and contributes to neurologic complications.

Show evidence (1 reference)

PMID:12720118 SUPPORT Other

"WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy."

The consensus definition supports monoclonal IgM production as a core downstream output of the malignant lymphoplasmacytic clone.

Serum Hyperviscosity

High circulating IgM burden increases serum viscosity and contributes to neurologic morbidity in a substantial subset of patients.

blood UBERON:0000178

Show evidence (1 reference)

PMID:18813229 SUPPORT Human Clinical

"Peripheral neuropathy occurs in nearly half of patients with this condition, and hyperviscosity-related nervous system disorders are encountered in up to a third."

This review supports serum hyperviscosity as a common intermediate pathogenic process contributing to WM neurologic morbidity.

MYD88 L265P Founder Mutation

MYD88 L265P is the dominant recurrent somatic lesion in WM and functions as an early oncogenic event in disease pathogenesis.

MYD88 hgnc:7562

Downstream

Bone Marrow Lymphoplasmacytic Infiltration MYD88-mutant clones participate in the core lymphoplasmacytic marrow disease state.

CXCR4 WHIM-like Subclonal Mutation Secondary CXCR4 mutations are commonly acquired after the MYD88 founder event.

Show evidence (1 reference)

PMID:24224040 SUPPORT Human Clinical

"These results suggest that the L265P mutation is involved in the majority of Waldenström's macroglobulinemia."

This patient-series abstract supports MYD88 L265P as a major recurrent driver lesion in WM.

CXCR4 WHIM-like Subclonal Mutation

A substantial subset of WM cases acquire subclonal WHIM-like CXCR4 mutations, adding heterogeneity to the MYD88-mutant clone and influencing treatment response.

CXCR4 hgnc:2561

Show evidence (1 reference)

PMID:26659815 SUPPORT Human Clinical

"By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM..."

This supports CXCR4 WHIM-like mutation as a recurrent, disease-enriched secondary genomic event in WM.

Mast Cell Supportive Signaling

Excess marrow mast cells provide trophic and survival signals to the lymphoplasmacytic clone, making the marrow microenvironment an active participant in WM pathogenesis.

mast cell CL:0000097 B cell CL:0000236

cell-cell signaling GO:0007267

bone marrow UBERON:0002371

Downstream

Bone Marrow Lymphoplasmacytic Infiltration Microenvironmental mast-cell signals support persistence of the malignant lymphoplasmacytic clone.

Show evidence (2 references)

PMID:18216294 SUPPORT In Vitro

"Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs."

This experiment supports a mechanistic microenvironment program in which WM-associated mast cells are induced to express trophic ligands.

PMID:18216294 SUPPORT Model Organism

"Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice."

This xenograft result supports the biologic importance of the CD27-CD70 microenvironment axis in sustaining WM disease progression.

✶

Histopathology

1

Lymphoplasmacytic Lymphoma OBLIGATE

The defining pathologic diagnosis in WM is lymphoplasmacytic lymphoma in the bone marrow, typically with an intertrabecular infiltrative pattern.

Show evidence (1 reference)

PMID:12720118 SUPPORT Other

"The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria."

Because the consensus definition states that the underlying pathologic diagnosis in WM is lymphoplasmacytic lymphoma, this histopathologic finding is OBLIGATE for the disease concept curated here.

⬡

Pathograph

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

●

Phenotypes

4

Blood 2

B-Cell Lymphoma HP:0012191

Show evidence (1 reference)

PMID:35087759 SUPPORT Human Clinical

"Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells."

Classifies lymphoplasmacytic lymphoma, the tissue-diagnosis counterpart of Waldenstrom macroglobulinemia, as a B-cell-derived non-Hodgkin lymphoma.

IgM Paraproteinemia OBLIGATE IgM heavy chain paraproteinemia HP:0020196

Show evidence (1 reference)

PMID:12720118 SUPPORT Other

"WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy."

The consensus definition makes IgM monoclonal gammopathy part of the defining disease concept, supporting an OBLIGATE IgM paraproteinemia phenotype.

Cardiovascular 1

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:18813229 SUPPORT Human Clinical

"Waldenström macroglobulinemia, a condition that most commonly occurs in lymphoplasmacytic lymphoma, typically manifests with diffuse lymphadenopathies, cytopenias, and a markedly elevated erythrocyte sedimentation rate."

This review directly lists diffuse lymphadenopathy among the typical WM clinical manifestations.

Nervous System 1

Peripheral Neuropathy FREQUENT HP:0009830

Show evidence (1 reference)

PMID:18813229 SUPPORT Human Clinical

"Peripheral neuropathy occurs in nearly half of patients with this condition, and hyperviscosity-related nervous system disorders are encountered in up to a third."

Nearly half of patients corresponds to about 50%, which falls in the FREQUENT band (30-79%).

🧬

Genetic Associations

2

MYD88 (Somatic Mutation)

Gene: MYD88 hgnc:7562 gene page

Show evidence (1 reference)

PMID:24224040 SUPPORT Human Clinical

"These results suggest that the L265P mutation is involved in the majority of Waldenström's macroglobulinemia."

This supports MYD88 L265P as the dominant recurrent somatic alteration in WM.

CXCR4 (Somatic Mutation)

Gene: CXCR4 hgnc:2561 gene page

Show evidence (1 reference)

PMID:26659815 SUPPORT Human Clinical

"The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis."

This supports CXCR4 mutation as a recurrent secondary somatic event in WM.

💊

Medical Actions

4

Watchful Waiting

Action: watchful waiting Ontology label: Supportive Care NCIT:C15747

Observation without immediate therapy is the standard disease-management strategy for asymptomatic WM without critically elevated IgM or compromised hematopoietic function.

Show evidence (1 reference)

PMID:37099027 SUPPORT Other

"The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function."

This consensus update supports watchful waiting as the standard management approach for asymptomatic WM.

Bendamustine-Rituximab

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: bendamustine CHEBI:135515 rituximab NCIT:C1702

Fixed-duration bendamustine-rituximab chemoimmunotherapy remains a central first-line option for symptomatic treatment-naive WM.

Show evidence (1 reference)

PMID:37099027 SUPPORT Other

"For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable."

The 2023 IWWM consensus panel identifies bendamustine-rituximab as a central fixed-duration first-line treatment option for symptomatic WM.

Zanubrutinib

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

Agent: zanubrutinib NCIT:C141428

Zanubrutinib is a covalent BTK inhibitor option for symptomatic WM and shows lower toxicity and deeper remissions than ibrutinib in the cited randomized trial update.

Show evidence (1 reference)

PMID:37099027 SUPPORT Other

"In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM."

This consensus update supports zanubrutinib as an evidence-based BTK inhibitor option for WM, with favorable efficacy and tolerability.

Plasmapheresis

Action: plasmapheresis Ontology label: Plasmapheresis NCIT:C15304

Plasmapheresis is used for rapid paraprotein reduction in hyperviscosity and related neurologic complications while systemic therapy addresses the underlying clone.

Show evidence (1 reference)

PMID:18813229 SUPPORT Human Clinical

"Treatment options, which should address both the paraprotein burden and the lymphoplasmacytic clone, include plasmapheresis and chemotherapy with alkylating agents, nucleoside analogs, and rituximab."

This review supports plasmapheresis as a disease-relevant intervention for rapid reduction of pathogenic paraprotein burden in WM.

📊

Related Datasets

6

Aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation precede malignancy in Waldenstrom macroglobulinemia geo:GSE179221

Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by the growth of mature IgM-expressing B cell clone predominantly in the bone marrow. Here we show that these disorders originate in the setting of expansion of genomically aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation that begins before the expansion of the malignant clone. Host response to these early lesions involves the induction of tumor-specific T cell immunity that may include MYD88 mutation-specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone.

human BULK RNA SEQ n=18

PMID:34778800

Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Aggressive gene expression signiture of waldenstrom macroglobulinemia with deletion 6q geo:GSE70511

Waldenstom macroglobulinemia (WM) with 6q del is still unknown. In the present study, we analyzed gene expression signiture of WM with 6q del. B-cell receptor signaling pathway, and IL21/IL21-R pathway were up-regulated in WM with 6q del.

human MICROARRAY n=8

PMID:30402490

Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Gene expression signature of bone lesion waldenstrom macroglobulinemia and myeloma geo:GSE70515

Bone lesion in waldenstom macroglobulinemia (WM) is less common. In the present study, we compaired gene expresion signature of bone lesion in WM compaired to multiple myeloma (MM). In WM, APRIL and HBGB1 were up-regulated compaired to MM.

human MICROARRAY n=7

Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Genetic landscape of Waldenstrom macroglobulinemia ega:EGAS00001003597

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Waldenstrom Macroglobulinemia"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Genetic and expression landscape of Waldenstrom macroglobulinemia ega:EGAS00001003603

Exome analyses for the identification of somatic mutation in Waldenstrom macroglobulinemia by comparison of tumor and CD3+(germ line control) population in 16 patients. transcription profiling of a series of Waldenstrom macroglobulinemia samples

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Waldenstrom Macroglobulinemia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

NCI Waldenstrom Macroglobulinemia Genome-wide Association Study dbgap:phs001284

A discovery GWAS is performed, consisting of genotyping 221 Waldenstrom macroglobulinemia (WM) cases on the Illumina Omni Express 12v1.1 platform and analyzing the genotypes together with those of 3798 previously genotyped controls in a model taking into account gender, age, and principal components of ancestry (i.e., significant eigenvectors). Directly genotyped data are supplemented by imputation using the Haplotype Reference Consortium.

Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Waldenstrom Macroglobulinemia"). Retrieved 2026-08-02.

{ }

Source YAML

click to show

name: Waldenstrom Macroglobulinemia
creation_date: '2026-04-13T05:35:14Z'
category: Cancer
categories:
- Hematologic Malignancy
- B-cell Neoplasm
- Non-Hodgkin Lymphoma
synonyms:
- Waldenström macroglobulinemia
- Waldenstrom's macroglobulinemia
- WM
description: >-
  Waldenstrom macroglobulinemia is an indolent B-cell neoplasm defined by bone
  marrow infiltration with lymphoplasmacytic lymphoma and secretion of a
  monoclonal IgM paraprotein. The disease is driven in most cases by MYD88
  L265P and further shaped in a substantial subset by subclonal CXCR4
  WHIM-like mutations. Morbidity reflects both marrow infiltration by the
  lymphoplasmacytic clone and the downstream effects of the IgM paraprotein,
  including hyperviscosity and peripheral neuropathy. Current disease-level
  management centers on observation for asymptomatic disease, fixed-duration
  chemoimmunotherapy, covalent BTK inhibition, and plasmapheresis for urgent
  paraprotein reduction.
disease_term:
  preferred_term: Waldenstrom macroglobulinemia
  term:
    id: MONDO:0100280
    label: Waldenstrom macroglobulinemia
parents:
- lymphoplasmacytic lymphoma
has_subtypes:
- name: Asymptomatic Waldenstrom Macroglobulinemia
  classification: clinical_course
  description: >-
    Asymptomatic WM is managed with observation rather than immediate therapy
    unless there is critically elevated IgM or compromised hematopoietic
    function.
  evidence:
  - reference: PMID:37099027
    reference_title: "Report of consensus panel 1 from the 11(th) International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The panel reiterated that watchful waiting remains the gold standard for
      asymptomatic patients without critically elevated IgM or compromised
      hematopoietic function.
    explanation: >-
      This consensus update supports asymptomatic WM as a clinically meaningful
      disease-course subtype defined by deferred treatment.
- name: Symptomatic Waldenstrom Macroglobulinemia
  classification: clinical_course
  description: >-
    Symptomatic WM is the treatment-requiring clinical subset distinguished from
    asymptomatic WM and precursor IgM-related states.
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Simple criteria to distinguish patients with symptomatic WM who require
      therapy from those with asymptomatic WM and MGUS were also proposed.
    explanation: >-
      This consensus definition supports symptomatic WM as a clinically distinct
      treatment-triggering subtype axis within the same disease entry.
- name: MYD88-mutant Waldenstrom Macroglobulinemia
  classification: molecular
  description: >-
    The dominant molecular subset of WM carries MYD88 L265P, an early oncogenic
    lesion that organizes the baseline disease program.
  genes:
  - preferred_term: MYD88
    term:
      id: hgnc:7562
      label: MYD88
  evidence:
  - reference: PMID:24224040
    reference_title: "L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that the L265P mutation is involved in the majority
      of Waldenström's macroglobulinemia.
    explanation: >-
      This supports a MYD88-mutant molecular subset that belongs inside the same
      disease page rather than as a separate dismech entry.
- name: CXCR4-mutated Waldenstrom Macroglobulinemia
  classification: molecular
  description: >-
    A treatment-relevant molecular subset of WM acquires subclonal WHIM-like
    CXCR4 mutations layered onto the core disease program.
  genes:
  - preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  evidence:
  - reference: PMID:26659815
    reference_title: "Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings show that CXCR4(WHIM) mutations are more common in WM than
      previously revealed, and are primarily subclonal, supporting their
      acquisition after MYD88(L265P) in WM oncogenesis.
    explanation: >-
      This supports CXCR4-mutated WM as a molecular facet subtype nested within
      the broader Waldenstrom disease graph.
definitions:
- name: Pathologic definition of Waldenstrom macroglobulinemia
  definition_type: CASE_DEFINITION
  description: >-
    Waldenstrom macroglobulinemia is a distinct clinicopathologic entity defined
    by bone marrow infiltration by lymphoplasmacytic lymphoma together with an
    IgM monoclonal gammopathy.
  scope: General clinicopathologic definition for disease-level curation
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      WM is an uncommon lymphoproliferative disorder characterized primarily by
      bone marrow infiltration and IgM monoclonal gammopathy.
    explanation: >-
      This consensus definition anchors WM as a disease entity defined by marrow
      lymphoplasmacytic infiltration together with IgM paraproteinemia.
pathophysiology:
- name: Bone Marrow Lymphoplasmacytic Infiltration
  description: >-
    The disease-defining tissue state is infiltration of the bone marrow by a
    clonal lymphoplasmacytic population spanning mature B-cell, plasmacytoid,
    and plasma-cell differentiation states.
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      WM is an uncommon lymphoproliferative disorder characterized primarily by
      bone marrow infiltration and IgM monoclonal gammopathy.
    explanation: >-
      The consensus definition identifies marrow infiltration as a primary
      clinicopathologic feature of WM.
  - reference: PMID:11718214
    reference_title: "Lymphoplasmacytic lymphoma/immunocytoma: towards a disease-targeted treatment?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lymphoplasmacytic-lymphoplasmacytoid lymphoma (LPL)/Waldenstrom's
      macroglobulinemia (WM) or immunocytoma (IMC) consists of diffuse
      proliferation of small mature B lymphocytes, plasmacytoid lymphocytes, and
      plasma-cells.
    explanation: >-
      This abstract specifies the marrow-infiltrating tumor-cell composition
      that underlies the lymphoplasmacytic clone in WM.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Monoclonal IgM Secretion
    description: The marrow lymphoplasmacytic clone gives rise to the circulating IgM paraprotein.
    evidence:
    - reference: PMID:12720118
      reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        WM is an uncommon lymphoproliferative disorder characterized primarily by
        bone marrow infiltration and IgM monoclonal gammopathy.
      explanation: >-
        This consensus definition supports the causal pairing of marrow
        lymphoplasmacytic disease with its defining IgM paraprotein output.
- name: Monoclonal IgM Secretion
  description: >-
    The clonal lymphoplasmacytic population produces a monoclonal IgM
    paraprotein that accumulates in the circulation and mediates important
    downstream complications.
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      WM is an uncommon lymphoproliferative disorder characterized primarily by
      bone marrow infiltration and IgM monoclonal gammopathy.
    explanation: >-
      The consensus definition supports monoclonal IgM production as a core
      downstream output of the malignant lymphoplasmacytic clone.
  cell_types:
  - preferred_term: IgM plasma cell
    term:
      id: CL:0000986
      label: IgM plasma cell
  biological_processes:
  - preferred_term: immunoglobulin production
    modifier: INCREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  locations:
  - preferred_term: blood serum
    term:
      id: UBERON:0001977
      label: blood serum
  downstream:
  - target: Serum Hyperviscosity
    description: Heavy circulating IgM burden increases serum viscosity and contributes to neurologic complications.
    evidence:
    - reference: PMID:18813229
      reference_title: "Neurological manifestations of Waldenström macroglobulinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Peripheral neuropathy occurs in nearly half of patients with this
        condition, and hyperviscosity-related nervous system disorders are
        encountered in up to a third.
      explanation: >-
        This clinical review directly documents hyperviscosity-related neurologic
        complications in WM; coupled with the disease-defining IgM paraprotein,
        it supports serum hyperviscosity as a downstream pathogenic process.
- name: Serum Hyperviscosity
  description: >-
    High circulating IgM burden increases serum viscosity and contributes to
    neurologic morbidity in a substantial subset of patients.
  evidence:
  - reference: PMID:18813229
    reference_title: "Neurological manifestations of Waldenström macroglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral neuropathy occurs in nearly half of patients with this
      condition, and hyperviscosity-related nervous system disorders are
      encountered in up to a third.
    explanation: >-
      This review supports serum hyperviscosity as a common intermediate
      pathogenic process contributing to WM neurologic morbidity.
  locations:
  - preferred_term: blood
    term:
      id: UBERON:0000178
      label: blood
- name: MYD88 L265P Founder Mutation
  description: >-
    MYD88 L265P is the dominant recurrent somatic lesion in WM and functions as
    an early oncogenic event in disease pathogenesis.
  genes:
  - preferred_term: MYD88
    term:
      id: hgnc:7562
      label: MYD88
  evidence:
  - reference: PMID:24224040
    reference_title: "L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that the L265P mutation is involved in the majority
      of Waldenström's macroglobulinemia.
    explanation: >-
      This patient-series abstract supports MYD88 L265P as a major recurrent
      driver lesion in WM.
  downstream:
  - target: Bone Marrow Lymphoplasmacytic Infiltration
    description: MYD88-mutant clones participate in the core lymphoplasmacytic marrow disease state.
    evidence:
    - reference: PMID:24224040
      reference_title: "L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These results suggest that the L265P mutation is involved in the majority
        of Waldenström's macroglobulinemia.
      explanation: >-
        This supports MYD88 L265P as a founding lesion contributing to the core
        marrow lymphoplasmacytic disease state.
  - target: CXCR4 WHIM-like Subclonal Mutation
    description: Secondary CXCR4 mutations are commonly acquired after the MYD88 founder event.
    evidence:
    - reference: PMID:26659815
      reference_title: "Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The findings show that CXCR4(WHIM) mutations are more common in WM than
        previously revealed, and are primarily subclonal, supporting their
        acquisition after MYD88(L265P) in WM oncogenesis.
      explanation: >-
        This directly supports CXCR4 mutation acquisition as a later subclonal
        branch layered onto the MYD88-mutant WM clone.
- name: CXCR4 WHIM-like Subclonal Mutation
  description: >-
    A substantial subset of WM cases acquire subclonal WHIM-like CXCR4
    mutations, adding heterogeneity to the MYD88-mutant clone and influencing
    treatment response.
  genes:
  - preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  evidence:
  - reference: PMID:26659815
    reference_title: "Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were
      identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated
      WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients,
      respectively, but no chronic lymphocytic leukaemia, multiple myeloma,
      non-IgM MGUS patients or healthy donors.
    explanation: >-
      This supports CXCR4 WHIM-like mutation as a recurrent, disease-enriched
      secondary genomic event in WM.
- name: Mast Cell Supportive Signaling
  description: >-
    Excess marrow mast cells provide trophic and survival signals to the
    lymphoplasmacytic clone, making the marrow microenvironment an active
    participant in WM pathogenesis.
  evidence:
  - reference: PMID:18216294
    reference_title: "CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC
      samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM
      as well as on LAD2 MCs.
    explanation: >-
      This experiment supports a mechanistic microenvironment program in which
      WM-associated mast cells are induced to express trophic ligands.
  - reference: PMID:18216294
    reference_title: "CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice
      with established WM using the SGN-70 antibody blocked disease progression
      in 12 of 12 mice, whereas disease progressed in all 5 untreated mice.
    explanation: >-
      This xenograft result supports the biologic importance of the CD27-CD70
      microenvironment axis in sustaining WM disease progression.
  cell_types:
  - preferred_term: mast cell
    term:
      id: CL:0000097
      label: mast cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: cell-cell signaling
    term:
      id: GO:0007267
      label: cell-cell signaling
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  downstream:
  - target: Bone Marrow Lymphoplasmacytic Infiltration
    description: Microenvironmental mast-cell signals support persistence of the malignant lymphoplasmacytic clone.
    evidence:
    - reference: PMID:18216294
      reference_title: "CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice
        with established WM using the SGN-70 antibody blocked disease progression
        in 12 of 12 mice, whereas disease progressed in all 5 untreated mice.
      explanation: >-
        Interrupting the mast-cell linked CD27-CD70 signaling axis reduced WM
        progression in vivo, partially supporting this pathway as an upstream
        contributor to persistence of the lymphoplasmacytic clone.
histopathology:
- name: Lymphoplasmacytic Lymphoma
  finding_term:
    preferred_term: Lymphoplasmacytic Lymphoma
    term:
      id: NCIT:C3212
      label: Lymphoplasmacytic Lymphoma
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    The defining pathologic diagnosis in WM is lymphoplasmacytic lymphoma in the
    bone marrow, typically with an intertrabecular infiltrative pattern.
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma
      as defined by the World Health Organization (WHO) and Revised
      European-American Lymphoma (REAL) classification criteria.
    explanation: >-
      Because the consensus definition states that the underlying pathologic
      diagnosis in WM is lymphoplasmacytic lymphoma, this histopathologic finding
      is OBLIGATE for the disease concept curated here.
phenotypes:
- category: Neoplastic
  name: B-Cell Lymphoma
  description: >-
    Waldenstrom macroglobulinemia is the IgM-secreting clinical syndrome of
    lymphoplasmacytic lymphoma, a neoplasm of mature B lymphocytes classified
    as a B-cell non-Hodgkin lymphoma.
  phenotype_term:
    preferred_term: B-cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  evidence:
  - reference: PMID:35087759
    reference_title: "Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived
      non-Hodgkin lymphoma characterized by the abnormal growth of transformed
      clonal lymphoplasmacytes and plasma cells.
    explanation: >-
      Classifies lymphoplasmacytic lymphoma, the tissue-diagnosis counterpart
      of Waldenstrom macroglobulinemia, as a B-cell-derived non-Hodgkin
      lymphoma.
- category: Hematologic
  name: IgM Paraproteinemia
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    A monoclonal IgM paraprotein is required for the disease concept curated
    here and reflects secretion by the lymphoplasmacytic clone.
  phenotype_term:
    preferred_term: IgM heavy chain paraproteinemia
    term:
      id: HP:0020196
      label: IgM heavy chain paraproteinemia
  evidence:
  - reference: PMID:12720118
    reference_title: "Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      WM is an uncommon lymphoproliferative disorder characterized primarily by
      bone marrow infiltration and IgM monoclonal gammopathy.
    explanation: >-
      The consensus definition makes IgM monoclonal gammopathy part of the
      defining disease concept, supporting an OBLIGATE IgM paraproteinemia
      phenotype.
- category: Lymphatic
  name: Lymphadenopathy
  description: >-
    Diffuse lymphadenopathy is a common manifestation of tissue involvement by
    the lymphoplasmacytic clone.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:18813229
    reference_title: "Neurological manifestations of Waldenström macroglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Waldenström macroglobulinemia, a condition that most commonly occurs in
      lymphoplasmacytic lymphoma, typically manifests with diffuse
      lymphadenopathies, cytopenias, and a markedly elevated erythrocyte
      sedimentation rate.
    explanation: >-
      This review directly lists diffuse lymphadenopathy among the typical WM
      clinical manifestations.
- category: Neurologic
  name: Peripheral Neuropathy
  frequency: FREQUENT
  description: >-
    Peripheral neuropathy is a major symptomatic complication of WM and often
    reflects the downstream consequences of the circulating IgM paraprotein.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:18813229
    reference_title: "Neurological manifestations of Waldenström macroglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral neuropathy occurs in nearly half of patients with this
      condition, and hyperviscosity-related nervous system disorders are
      encountered in up to a third.
    explanation: >-
      Nearly half of patients corresponds to about 50%, which falls in the
      FREQUENT band (30-79%).
genetic:
- name: MYD88
  gene_term:
    preferred_term: MYD88
    term:
      id: hgnc:7562
      label: MYD88
  association: Somatic Mutation
  notes: >-
    MYD88 L265P is the dominant recurrent somatic lesion in WM and is treated
    here as an upstream founder event in disease oncogenesis.
  evidence:
  - reference: PMID:24224040
    reference_title: "L265P mutation of the MYD88 gene is frequent in Waldenström's macroglobulinemia and its absence in myeloma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that the L265P mutation is involved in the majority
      of Waldenström's macroglobulinemia.
    explanation: >-
      This supports MYD88 L265P as the dominant recurrent somatic alteration in WM.
- name: CXCR4
  gene_term:
    preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  association: Somatic Mutation
  notes: >-
    WHIM-like CXCR4 mutations occur in a substantial subset of WM cases and are
    primarily subclonal, consistent with later acquisition after MYD88.
  evidence:
  - reference: PMID:26659815
    reference_title: "Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings show that CXCR4(WHIM) mutations are more common in WM than
      previously revealed, and are primarily subclonal, supporting their
      acquisition after MYD88(L265P) in WM oncogenesis.
    explanation: >-
      This supports CXCR4 mutation as a recurrent secondary somatic event in WM.
treatments:
- name: Watchful Waiting
  description: >-
    Observation without immediate therapy is the standard disease-management
    strategy for asymptomatic WM without critically elevated IgM or compromised
    hematopoietic function.
  treatment_term:
    preferred_term: watchful waiting
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37099027
    reference_title: "Report of consensus panel 1 from the 11(th) International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The panel reiterated that watchful waiting remains the gold standard for
      asymptomatic patients without critically elevated IgM or compromised
      hematopoietic function.
    explanation: >-
      This consensus update supports watchful waiting as the standard management
      approach for asymptomatic WM.
- name: Bendamustine-Rituximab
  description: >-
    Fixed-duration bendamustine-rituximab chemoimmunotherapy remains a central
    first-line option for symptomatic treatment-naive WM.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: bendamustine
      term:
        id: CHEBI:135515
        label: bendamustine
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:37099027
    reference_title: "Report of consensus panel 1 from the 11(th) International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For first-line treatment, chemoimmunotherapy (CIT) regimens such as
      dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine,
      rituximab (Benda-R) continue to play a central role in managing WM, as
      they are effective, of fixed duration, generally well-tolerated, and
      affordable.
    explanation: >-
      The 2023 IWWM consensus panel identifies bendamustine-rituximab as a
      central fixed-duration first-line treatment option for symptomatic WM.
- name: Zanubrutinib
  description: >-
    Zanubrutinib is a covalent BTK inhibitor option for symptomatic WM and shows
    lower toxicity and deeper remissions than ibrutinib in the cited randomized
    trial update.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: zanubrutinib
      term:
        id: NCIT:C141428
        label: Zanubrutinib
  evidence:
  - reference: PMID:37099027
    reference_title: "Report of consensus panel 1 from the 11(th) International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In a Phase III randomized trial updated at IWWM-11, the second-generation
      cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper
      remissions, thus categorizing zanubrutinib as a suitable treatment option
      in WM.
    explanation: >-
      This consensus update supports zanubrutinib as an evidence-based BTK
      inhibitor option for WM, with favorable efficacy and tolerability.
- name: Plasmapheresis
  description: >-
    Plasmapheresis is used for rapid paraprotein reduction in hyperviscosity and
    related neurologic complications while systemic therapy addresses the
    underlying clone.
  treatment_term:
    preferred_term: plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:18813229
    reference_title: "Neurological manifestations of Waldenström macroglobulinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment options, which should address both the paraprotein burden and
      the lymphoplasmacytic clone, include plasmapheresis and chemotherapy with
      alkylating agents, nucleoside analogs, and rituximab.
    explanation: >-
      This review supports plasmapheresis as a disease-relevant intervention for
      rapid reduction of pathogenic paraprotein burden in WM.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100280
      label: Waldenstrom macroglobulinemia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this Waldenstrom macroglobulinemia entry.
datasets:
- accession: geo:GSE179221
  title: Aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation precede malignancy in Waldenstrom macroglobulinemia
  description: Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by the growth of mature IgM-expressing B cell clone predominantly in the bone marrow. Here we show that these disorders originate in the setting of expansion of genomically aberrant extrafollicular B cells, immune dysfunction and myeloid inflammation that begins before the expansion of the malignant clone. Host response to these early lesions involves the induction of tumor-specific T cell immunity that may include MYD88 mutation-specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 18
  publication: PMID:34778800
  notes: Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE70511
  title: Aggressive gene expression signiture of waldenstrom macroglobulinemia with deletion 6q
  description: Waldenstom macroglobulinemia (WM) with 6q del is still unknown. In the present study, we analyzed gene expression signiture of WM with 6q del. B-cell receptor signaling pathway, and IL21/IL21-R pathway were up-regulated in WM with 6q del.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 8
  publication: PMID:30402490
  notes: Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE70515
  title: Gene expression signature of bone lesion waldenstrom macroglobulinemia and myeloma
  description: Bone lesion in waldenstom macroglobulinemia (WM) is less common. In the present study, we compaired gene expresion signature of bone lesion in WM compaired to multiple myeloma (MM). In WM, APRIL and HBGB1 were up-regulated compaired to MM.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 7
  notes: Identified by GEO DataSets index search for Waldenstrom Macroglobulinemia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003597
  title: Genetic landscape of Waldenstrom macroglobulinemia
  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 ("Waldenstrom Macroglobulinemia"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003603
  title: Genetic and expression landscape of Waldenstrom macroglobulinemia
  description: Exome analyses for the identification of somatic mutation in Waldenstrom macroglobulinemia by comparison of tumor and CD3+(germ line control) population in 16 patients. transcription profiling of a series of Waldenstrom macroglobulinemia samples
  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 ("Waldenstrom Macroglobulinemia"); 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: dbgap:phs001284
  title: NCI Waldenstrom Macroglobulinemia Genome-wide Association Study
  description:  A discovery GWAS is performed, consisting of genotyping 221 Waldenstrom macroglobulinemia (WM) cases on the Illumina Omni Express 12v1.1 platform and analyzing the genotypes together with those of 3798 previously genotyped controls in a model taking into account gender, age, and principal components of ancestry (i.e., significant eigenvectors). Directly genotyped data are supplemented by imputation using the Haplotype Reference Consortium.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Waldenstrom Macroglobulinemia"). Retrieved 2026-08-02.
discussions:
- discussion_id: wm_wnk2_kd_lacking_isoform_signaling
  prompt: >-
    Does a WNK2 isoform that carries the recurrent exon 27-28 skip and lacks the
    kinase domain (it starts from an internal transcription start site), and that
    WM tumor cells express at high levels, drive ERK1/2 and NF-κB signaling in
    Waldenström macroglobulinemia, and is that axis separable from MYD88 itself?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#MYD88 L265P Founder Mutation
  rationale: >-
    The entry's pathophysiology places MYD88 L265P upstream of the malignant
    clone but does not carry the WNK2 isoform story. Guerrera et al. (PMID:42420257)
    report that novel cancer-specific WNK2 isoforms are highly expressed by WM
    tumor cells, that the kinase-domain-lacking isoform WNK2/S-NK1 is the most
    expressed of the kinase-domain-lacking isoforms in WM, and that it activates
    ERK1/2 and NF-κB, unlike the canonical full-length kinase, which inhibits
    ERK1/2 in a kinase-dependent manner. The same study reports a MYD88-independent
    route to WNK2 dysregulation, likely linked to aberrant methylation: MYD88 L265P
    overexpression in OCI-LY7 and Ramos did not raise WNK2. These are findings from
    tumor cells and cell-line work reported in one study. What is missing is how
    the kinase-domain-lacking isoform signals, what drives its splicing in WM cells,
    and whether this axis can be targeted separately from MYD88 inhibition, given
    that no WNK2-selective inhibitor currently exists.
  proposed_experiments:
  - experiment_id: wm_wnk2_s_nk1_isoform_rescue
    name: Isoform-specific rescue in MYD88-mutant WM cells
    description: >-
      Express the kinase-domain-lacking WNK2 isoform in a MYD88 wild-type
      background and in MYD88 L265P cells with isoform-specific knockdown, then
      read ERK1/2 and NF-κB activity. This separates the isoform's effect from
      MYD88-driven signaling.
  evidence:
  - reference: PMID:42420257
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    reference_title: "WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia."
    snippet: "Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling."
    explanation: Lentiviral overexpression of the kinase-domain-lacking isoform in WM cell lines activated ERK1/2 and NF-κB signaling.
  - reference: PMID:42420257
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    reference_title: "WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia."
    snippet: "WNK2 negatively regulates ERK1/2 activation in a kinase-dependent manner through RHOA/RAC1 modulation of PAK1"
    explanation: Prior cell work the paper cites for the inhibitory role of the canonical kinase-domain isoform on ERK1/2.
  - reference: PMID:42420257
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    reference_title: "WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia."
    snippet: "Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM."
    explanation: Patient-derived expression profiling across 264 untreated WM cases shows WNK2 dysregulation from early disease.
  - reference: PMID:42420257
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    reference_title: "WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia."
    snippet: "WNK2 levels did not increase following either MYD88MUT overexpression in endogenously MYD88WT OCI-LY7 and Ramos"
    explanation: Overexpressing MYD88 L265P in MYD88-wild-type lines did not raise WNK2, which bears on whether the axis is MYD88-independent.
  - reference: PMID:42420257
    supports: SUPPORT
    evidence_source: OTHER
    reference_title: "WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia."
    snippet: "Unfortunately, pharmacological targeting of WNK2 is currently not achievable due to the lack of WNK2-selective inhibitors."
    explanation: The paper states that no WNK2-selective inhibitor is available, which is why the gap asks whether the axis can be targeted separately.
  notes: >-
    The source reports that the S-K and S-NK exon 27-28 skipping families are
    also upregulated in cholangiocarcinoma, and that S-NK transcripts are present
    in normal colon, so these isoforms are not WM-specific. The functional data
    come from lentiviral transduction of WM cell lines.

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References & Deep Research

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Waldenstrom Macroglobulinemia: Mechanistic Summary

n/a 7 citations 2026-04-13T05:35:00Z

Waldenstrom Macroglobulinemia: Mechanistic Summary

Disease anchor and modeling choice

Waldenstrom macroglobulinemia (WM) is best modeled here as a single disease-level mechanism graph rooted to MONDO:0100280 Waldenstrom macroglobulinemia, not as a lattice of every oncology subclass. The key defining combination is:

lymphoplasmacytic lymphoma involving the bone marrow
secretion of a monoclonal IgM paraprotein
recurrent MYD88-driven B-cell oncogenesis with CXCR4-mutant subclonal evolution

Following issue #1198, I treated lymphoplasmacytic lymphoma as the disease parent / diagnostic histopathology concept rather than opening a separate dismech page for every related ontology refinement. Likewise, I did not split smoldering WM, familial WM, refractory WM, recurrent WM, or transformed WM into separate disorder files, because those are disease-state, predisposition, or transformation facets rather than distinct causal programs for the baseline WM mechanism graph. In the YAML, this was reflected by keeping one disease page and encoding subtype structure only as flat has_subtypes facets for clinical course and molecular context.

Relevant ontology anchors:

MONDO:0100280 Waldenstrom macroglobulinemia
MONDO:0000432 lymphoplasmacytic lymphoma
NCIT:C80307 Waldenstrom Macroglobulinemia
NCIT:C3212 Lymphoplasmacytic Lymphoma

Foundational disease definition

PMID:12720118 remains the key disease-definition paper for this curation. It defines WM as an uncommon lymphoproliferative disorder characterized by bone marrow lymphoplasmacytic infiltration and IgM monoclonal gammopathy, and it explicitly argues that WM is a distinct clinicopathologic entity rather than just an IgM secretion syndrome.

PMID:11718214 complements this by describing the underlying cell composition: small mature B lymphocytes, plasmacytoid lymphocytes, and plasma cells. For the dismech entry, that supports treating the bone-marrow lymphoplasmacytic clone as the core disease unit and the IgM paraprotein as a downstream biochemical output of that clone.

Core mechanisms selected for the YAML graph

1. Bone marrow lymphoplasmacytic infiltration

This is the disease-defining tissue state. The mechanistic unit is the marrow infiltrating clone composed of B-cell/plasma-cell lineage lymphoplasmacytic cells. This node should sit near the top of the graph because it links the founding genomic lesions to the clinical consequences of marrow occupation and paraprotein secretion.

Key support:

PMID:12720118
PMID:11718214

2. Monoclonal IgM secretion

The IgM paraprotein is the key biochemical output of the malignant clone and is best modeled as a separate downstream node rather than bundled into the marrow infiltration node. This helps keep the graph atomic and allows direct edges to paraprotein-driven complications.

Key support:

PMID:12720118

3. Serum hyperviscosity

Hyperviscosity is a downstream biophysical consequence of heavy circulating IgM burden. I modeled this as a separate pathophysiology node rather than collapsing it into the phenotype list, because it is an intermediate pathogenic process that explains neurologic and visual symptoms.

Key support:

PMID:18813229

4. MYD88 L265P founder mutation

MYD88 L265P is the dominant recurrent somatic lesion in WM and should be treated as an upstream genomic driver node. The cached abstract set supports two important, conservative claims:

MYD88 L265P is present in the majority of WM cases (PMID:24224040)
CXCR4 WHIM-like mutations are usually acquired after MYD88 L265P in WM oncogenesis (PMID:26659815)

Because the cached abstract set was used conservatively, I did not overstate the full MYD88 -> BTK -> IRAK -> NF-kB signaling chain in the YAML evidence block without a validated PMID cache line for that exact claim. That mechanistic detail is real and well-supported in the broader WM literature, but the YAML entry is restricted to what could be quoted exactly and validated in this branch.

5. CXCR4 WHIM-like subclonal evolution

CXCR4 mutations are not the founding lesion; they are modeled as a later, subclonal branch layered onto the MYD88-mutant clone. This is a good example of an oncology refinement that belongs inside the same disease graph rather than in a separate disease page.

Key support:

PMID:26659815
PMID:37099027 (clinical relevance for BTK-inhibitor sensitivity)

6. Mast-cell supportive signaling in the marrow microenvironment

PMID:18216294 shows that excess marrow mast cells are common in WM and provide growth/survival signals to lymphoplasmacytic cells. This is worth a separate node because it captures a bona fide microenvironmental mechanism rather than a mere descriptive pathology feature.

Key support:

PMID:18216294

Clinical phenotype and complication summary

The best abstract-backed phenotype set from the cached reference slice is:

IgM paraproteinemia / monoclonal gammopathy (PMID:12720118)
lymphadenopathy (PMID:18813229)
peripheral neuropathy, occurring in nearly half of patients (PMID:18813229)

Hyperviscosity-related neurologic disorders are common enough to matter mechanistically but were better represented as a downstream pathophysiology node than as an HP-grounded phenotype because the available ontology grounding in this schema is much cleaner for the manifestations than for the syndrome label itself.

Treatment conclusions for the entry

The current disease-level treatment section should emphasize:

watchful waiting for asymptomatic patients, per the 2023 IWWM consensus (PMID:37099027)
fixed-duration chemoimmunotherapy as an important first-line option, especially bendamustine-rituximab (PMID:37099027)
zanubrutinib as a current covalent BTK inhibitor option with lower toxicity and deeper remissions than ibrutinib in the referenced randomized-trial update (PMID:37099027)
plasmapheresis for rapid paraprotein reduction in hyperviscosity and related neurologic complications (PMID:18813229)

Following #1198, NCIT should be preferred where it gives materially better oncology specificity. In the YAML this means:

NCIT:C3212 for the histopathology finding
NCIT:C1702 for rituximab
NCIT:C141428 for zanubrutinib
NCIT:C15304 for plasmapheresis

I initially attempted to ground BR and zanubrutinib with NCIT regimen terms as well, but the current RegimenTerm validator expansion in this branch did not accept those codes, so I retained the validated disease-level treatment representation using treatment actions plus ontology-grounded agents/procedures.

References

PMID:11718214
PMID:12720118
PMID:18216294
PMID:18813229
PMID:24224040
PMID:26659815
PMID:37099027

Waldenstrom Macroglobulinemia

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References & Deep Research

Deep Research

Waldenstrom Macroglobulinemia: Mechanistic Summary

Disease anchor and modeling choice

Foundational disease definition

Core mechanisms selected for the YAML graph

1. Bone marrow lymphoplasmacytic infiltration

2. Monoclonal IgM secretion

3. Serum hyperviscosity

4. MYD88 L265P founder mutation

5. CXCR4 WHIM-like subclonal evolution

6. Mast-cell supportive signaling in the marrow microenvironment

Clinical phenotype and complication summary

Treatment conclusions for the entry

References