Myeloid/Lymphoid Neoplasms with ETV6-JAK2
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Primary Author(s)*
Lauren R. Crowson-Hindman, DO, MS and Daynna J. Wolff, PhD
Cancer Category/Type
Acute myeloid leukemia/ myeloid/lymphoid neoplasms
Cancer Sub-Classification / Subtype
Myeloid/Lymphoid neoplasms with eosinophilia and gene rearrangement
Definition / Description of Disease
A rare myeloproliferative neoplasm comprised of pluripotent (lymphoid-myeloid) stem cells and variably associated with hypereosinophilic syndromes, with t(9;12)(p24.1;p13.2) resulting in fusion between ETV6 and JAK2 genes, leading to the expression of an aberrant tyrosine kinase[1][2].
This entity is uncommon and not included as a formal entity in the WHO myeloid/lymphoid with eosinophilia classification[1].
Synonyms / Terminology
Myeloid and lymphoid neoplasms associated with JAK2 rearrangement
Epidemiology / Prevalence
This disease is rare with 8 cases reported in the 2017 WHO Classification and 12 reported by Cook et al[1][3]. The incidence of hypereosinophilia in general is only 0.036 per 100,000 and genetic causes represent only a small portion of these cases[4].
Clinical Features
Myeloid and lymphoid malignancies associated with ETV6-JAK2 rearrangements include most commonly B-lymphoblastic leukemia (B-ALL) and T-lymphoblastic lymphoma/leukemia, and also MDS/MPN neoplasms and atypical chronic myeloid leukemia (CML)[1][3]; see Table 1. Clinicopathologic details of prior cases reported to contain ETV6-JAK2 fusions[3]. Cases of B-lymphoblastic leukemia/lymphoma may have features of BCR-ABL1-like lymphoblastic leukemia[1]. Patients rarely present with eosinophilia, and splenomegaly is a variable clinical finding[1][3].
Sites of Involvement
Peripheral blood and bone marrow
Morphologic Features
The small group of disorders is more heterogeneous than cases with PCM1-JAK2[1]. The BCR-JAK2 fusion causes a genetic alteration at the pluripotent lymphoid-myeloid stem cell stage, thus causing both myeloid and lymphoid neoplasms. Eosinophilia and neutrophil precursors may be present in the peripheral blood. Patients often have hypercellular bone marrow with eosinophils and fibrosis; dyserythropoiesis and dysgranulopoiesis are uncommon but may occur. Monocytosis is uncommon[1].
Immunophenotype
Immunophenotypic analysis may be useful in characterizing lymphoid components or monitoring for acute myeloid transformation[1].
Chromosomal Rearrangements (Gene Fusions)
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| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Prevalence |
|---|---|---|
| t(9;12)(p24.1;p13.2) | ETV6-JAK2 | Rare |
Characteristic Chromosomal Aberrations / Patterns
There are no known secondary chromosomal changes or pattern of other chromosome aberrations
Genomic Gain/Loss/LOH
There are no known recurrent genomic loss/gain or LOH patterns associated with this entity.
Gene Mutations (SNV/INDEL)
There are no known recurrent aberrations.
Epigenomics (Methylation)
There are no known epigenomic modifiers.
Genes and Main Pathways Involved
Chromosomal translocations can lead to gene fusions such as ETV6–JAK2, BCR–JAK2, SSBP2–JAK2, PAX-5–JAK2, etc., that are associated with varying myeloid and lymphoid malignancies of aggressive nature[5].
JAK2 (janus kinase 2) is a tyrosine kinase responsible for the activation of the JAK-STAT pathway which mediates tyrosine phosphorylation, leading to cell differentiation and proliferation. Chromosomal translocations can lead to fusions that produce aberrant tyrosine kinase and result in constitutive activation of the JAK-STAT pathway. Both fusion proteins BCR-JAK2 and ETV6-JAK2 include the JH1 domain of JAK2, which is considered the catalytic domain and determines the activity potential of JAK2. The consequences of the aberrant JAK2 activation are neoplastic transformation and abnormal cell proliferation[6].
Diagnostic Testing Methods
Morphologic evaluation and flow cytometric immunophenotyping in conjunction with cytogenetic analysis, fluorescence in situ hybridization (FISH) and genetic testing are all required to identify molecular abnormalities in such variable clinical/hematologic presentations[2]. RT-PCR can identify in-frame transcripts of ETV6-JAK2 fusions, and FISH analyses of BCR/ABL1, PDGFRA, PDGFRB, FGFR1, JAK2 gene regions can be used[3].
Diagnostic algorithm for hypereosinophilia, including eosinophilia-associated neoplasms[2].
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
With this being such a rare entity, prognostic and therapeutic data is scarce. An aggressive disease course with variable sensitivity to current TK inhibitors has been reported[2]. Stem cell transplant may be the ultimate therapy of choice, with one case reported remaining disease-free for up over three years after transplant[7].
Familial Forms
No familial forms have been documented.
Other Information
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Links
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References
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- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Bain BJ, et al., (2017). Myeloid/lymphoid neoplasms with PDGFRA rearrangement 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, p72-79.
- ↑ 2.0 2.1 2.2 2.3 Reiter, Andreas; et al. (2017-02-09). "Myeloid neoplasms with eosinophilia". Blood. 129 (6): 704–714. doi:10.1182/blood-2016-10-695973. ISSN 0006-4971.
- ↑ 3.0 3.1 3.2 3.3 3.4 Cook, James R.; et al. (2020). "Myeloid neoplasm with eosinophilia and ETV6-JAK2 fusion". Leukemia & Lymphoma. 61 (1): 213–216. doi:10.1080/10428194.2019.1658105. ISSN 1042-8194.
- ↑ Crane, Martin M.; et al. (2010-07). "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. ISSN 0091-6749. PMC 5781228. PMID 20639012. Check date values in:
|date=(help)CS1 maint: PMC format (link) - ↑ Angelova, Svetlana; et al. (2011). "Chromosomal translocation t(9;22)(p24;q11) appears to be recurrently associated with myeloid malignancy with aggressive course". Leukemia & Lymphoma. 52 (9): 1809–1810. doi:10.3109/10428194.2011.580025. ISSN 1042-8194.
- ↑ Xu, Yang; et al. (2013). "A BCR–JAK2 fusion gene from ins(22;9)(q11;p13p24) in a patient with atypical chronic myeloid leukemia". Leukemia & Lymphoma. 54 (10): 2322–2324. doi:10.3109/10428194.2012.762648. ISSN 1042-8194.
- ↑ 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.
Notes
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