Myeloid/Lymphoid Neoplasms with PCM1-JAK2
editPREVIOUS EDITIONThis page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.
Primary Author(s)*
Jessica Snider, M.D. and Daynna J. Wolff, PhD
Cancer Category/Type
Acute Myeloid Leukemia/Myeloid/lymphoid neoplasm with eosinophilia
Cancer Sub-Classification / Subtype
PCM1/JAK2-Mediated myeloid/lymphoid neoplasm with eosinophilia
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.[1][2][3]
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 these[4]There is a significant male predominance with a median age of 47 years old (age range 7-77)[1] As of August 2018, only 40 cases had been reported[5]
Clinical Features
Patients typically present with features of a myeloproliferative disorder or MDS/MPN and most have eosinophilia and/or bone marrow fibrosis[5][6]. Patients in chronic phase tend to progress to AML quickly; some present with de novo acute leukemia, either myeloid or lymphoid[6][5]
In general, patients with this disorder have weakness/fatigue (~26%), cough (~24%), myaligias/angioedema (~14%), rash or fever (~12%) and rhinitis (~10%)[7] ; lymphadenopathy and splenomegaly are common[5]
Sites of Involvement
Peripheral blood and bone marrow
Morphologic Features
Patients often have a hypercellular bone marrow with increased eosinophils and fibrosis[1][5].Increased granuolpoiesis with eosinophilia and neutrophil precursors, including myeloblasts[1][5]. Dyserythropoiesis and dysgranulopoiesis are not typical but may be observed[1][5] 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
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[1]. In addition, For the cases with lymphoid components, IHC can assist with assessment and show dim CD19 and dim CD10, consistent with lymphoblast lineage[1][5].
Chromosomal Rearrangements (Gene Fusions)
| 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 |
Characteristic Chromosomal Aberrations / Patterns
There are no known secondary chromosomal changes and no pattern of other chromosome aberrations.
Genomic Gain/Loss/LOH
There are no known recurrent genomic loss/gain or LOH pattern associated with entity.
Gene Mutations (SNV/INDEL)
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[5]
Other Mutations
Epigenomics (Methylation)
There are no known epigenomic modifiers.
Genes and Main Pathways Involved
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[6]
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.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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[5]. 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
Familial Forms
No familial forms have been documented.
Other Information
Links
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Bain BJ, Horny HP, Arber DA, et al. Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1, or with PCM1-JAK2., in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
- ↑ Reiter, Andreas; et al. (2017). "Myeloid neoplasms with eosinophilia". Blood. 129 (6): 704–714. doi:10.1182/blood-2016-10-695973. ISSN 0006-4971.
- ↑ Baer, Constance; et al. (2018). "Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2". Haematologica. 103 (8): e348–e350. doi:10.3324/haematol.2017.187302. ISSN 0390-6078. PMC 6068021. PMID 29567772.CS1 maint: PMC format (link)
- ↑ Crane, Martin M.; et al. (2010). "Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence". Journal of Allergy and Clinical Immunology. 126 (1): 179–181. doi:10.1016/j.jaci.2010.03.035. PMC 5781228. PMID 20639012.CS1 maint: PMC format (link)
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Tang, Guilin; et al. (2019). "Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study". Modern Pathology. 32 (4): 490–498. doi:10.1038/s41379-018-0165-9. ISSN 0893-3952.
- ↑ 6.0 6.1 6.2 Hoeller, Sylvia; et al. (2011). "PCM1–JAK2-fusion: a potential treatment target in myelodysplastic–myeloproliferative and other hemato-lymphoid neoplasms". Expert Opinion on Therapeutic Targets. 15 (1): 53–62. doi:10.1517/14728222.2011.538683. ISSN 1472-8222.
- ↑ Gotlib, Jason (2017). "World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management". American Journal of Hematology. 92 (11): 1243–1259. doi:10.1002/ajh.24880.
Notes
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