HAEM5:Myeloid/lymphoid neoplasm with JAK2 rearrangement

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Myeloid/Lymphoid Neoplasms with PCM1-JAK2.

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Primary Author(s)*

Jessica Snider, M.D. and Daynna J. Wolff, PhD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Myeloid/lymphoid neoplasms
Type	Myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangement
Subtype(s)	Myeloid/lymphoid neoplasm with JAK2 rearrangement

Definition / Description of Disease

A hematologic neoplasm comprised of pluripotent (lymphoid-myeloid) stem cells characteristically seen with eosinophilia that result from the formation of a fusion between the PCM1 and JAK2 genes, leading to the expression of an aberrant tyrosine kinase. Due to its pluripotent nature, the hematologic stem cells can give rise to eosinophils, neutrophils, B-lymphoid and T-lymphoid cells. The presence of eosinophilia is not required for the diagnosis.

Synonyms / Terminology

Chronic eosinophilic leukemia with PCM1/JAK2

PCM1/JAK2 –associated chronic eosinophilic leukemia

Myeloid and lymphoid neoplasms associated with JAK2 rearrangement

JAK2-associated Hypereosinophilic syndrome

Myeloid and lymphoid neoplasms with JAK2 rearrangement

Myeloproliferative variant of the hypereosinophilic syndrome

Epidemiology / Prevalence

This disease is rare; the incidence of hypereosinophilia in general is only 0.036 per 100,000 and genetic causes represent only a small portion of theseThere is a significant male predominance with a median age of 47 years old (age range 7-77) As of August 2018, only 40 cases had been reported

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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Patients typically present with features of a myeloproliferative disorder or MDS/MPN and most have eosinophilia and/or bone marrow fibrosis. Patients in chronic phase tend to progress to AML quickly; some present with de novo acute leukemia, either myeloid or lymphoid 

In general, patients with this disorder have weakness/fatigue (~26%), cough (~24%), myaligias/angioedema (~14%), rash or fever (~12%) and rhinitis (~10%) ; lymphadenopathy and splenomegaly are common

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Sites of Involvement

Peripheral blood and bone marrow

Morphologic Features

Patients often have a hypercellular bone marrow with increased eosinophils and fibrosis.Increased granuolpoiesis with eosinophilia and neutrophil precursors, including myeloblasts. Dyserythropoiesis and dysgranulopoiesis are not typical but may be observed Increased lymphoblasts may also be seen with blast cells having high nuclear to cytoplasmic ratios and open chromatin. If eosinophilia is present, it is comprised mainly of mature eosinophils with scattered immature forms. Eosinophilic abnormalities can be seen and include sparse granulation with small forms, vacuoles in the cytoplasm, increased eosinophil size, and nuclear hypo- and hypersegmentation.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

editv4:Immunophenotype

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IHC can be used to characterize acute myeloid transformation and myeloblasts express dim CD45, dim CD34, dim CD117, HLA-DR, dim CD33, and dim CD13. In addition, For the cases with lymphoid components, IHC can assist with assessment and show dim CD19 and dim CD10, consistent with lymphoblast lineage.

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Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(8;9)(p22;p24.1)	3'JAK2 / 5'PCM1	der(8)	rare

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Most patients present with MPN with variable degrees of eosinophilia in blood and/or bone marrow, frequent marrow fibrosis, and large aggregates of immature erythroid precursors, and clinically exhibit hepatosplenomegagly and lymphadenopathy. However, diagnosis may be difficult in cases without obvious eosinophilia.

Due to the variations in presentation, the prognosis is mainly dependent on the phase at presentation, but generally tends to have an aggressive course¹. There currently are no approved therapies for PCM1/JAK2-mediated myeloid/lymphoid neoplasm with eosinophilia; however, JAK2 inhibitors have been approved for other hematopoietic neoplasms with constitutively activated JAK2 kinases.²

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Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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There are no known recurrent genomic loss/gain or LOH pattern associated with entity.

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Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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There are no known secondary chromosomal changes and no pattern of other chromosome aberrations.

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Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Given the rarity of the entity, there are no known recurrent aberrations. For the largest series studied, most cases were negative for mutations. However, some cases showed variants in genes associated with myeloid malignancies (ASXL1, RUNX1, SRSF2, TET2, BCOR) and one patient with B-ALL transformation showed variants in ETV6 and TP53

Other Mutations

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Epigenomic Alterations

There are no known epigenomic modifiers.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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PCM1 (pericentriolar material 1) is a protein present in cytoplasmic granules and can be found in association with the centrosome. PCM1 is indirectly responsible for microtubule anchoring, which is necessary for a variety of cellular functions, including intracellular transport and cell division. The gene is located at band 8p22 and includes 41 exons.⁵

JAK2 (janus kinase 2) is a tyrosine kinase responsible for activation of the JAK-STAT pathway by mediating tyrosine phosphorylation, leading to cell proliferation and differentiation. Constitutive activation of JAK2 can result from chromosomal translocations and lead to uncontrolled proliferation of hematopoietic cells. The gene is located at band 9p24.1 and includes 25 exons.⁶

The PCM1-JAK2 fusion product retains the coiled-coil domains of PCM1 and the activating tyrosine kinase domain of JAK2. Thus PCM1-JAK2 fusion produces an aberrant tyrosine kinase that results in constitutive activation of the JAK2–STAT pathway

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Genetic Diagnostic Testing Methods

Diagnosis of this entity is made when a chromosome analysis showing a t(8;9) correlates with the clinical and morphological phenotype of the patient and/or when the fusion is confirmed by ancillary testing. FISH with a dual color, dual fusion probe for PCM1-JAK2 and sequencing of RNA to detect the functional fusion are the most commonly used methods to confirm this diagnosis. FISH with a JAK2 break-apart probe may also provide useful information to confirm a diagnosis.

However, because the clinical presentation can vary and this disease can show many overlapping morphological features of other entities, the PCM1-JAK2 fusion or 8;9 translocation may be detected without overt suspicion. Therefore, agnostic genomic methods such as large panels of RNA fusions known to be associated with myeloid or lymphoid malignancies, whole exome/genome sequencing and occasionally chromosomal microarray analysis may provide evidence for this diagnosis.

Familial Forms

No familial forms have been documented.

Links

HAEM4:Myeloid/Lymphoid Neoplasms with Eosinophilia and Rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2

PCM1

JAK2

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Myeloid/lymphoid neoplasm with JAK2 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Myeloid/lymphoid_neoplasm_with_JAK2_rearrangement.