Myeloid/Lymphoid Neoplasms with BCR-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;22)(p24.1;p11.2) resulting in fusion between BCR 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 11 cases reported in the 2017 WHO Classification and 15 reported by He 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]. The median patient age is 51 years old with a slight male predominance, 2:1[3].
Clinical Features
Myeloid and lymphoid malignancies associated with BCR-JAK2 rearrangements include myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) being the most common, as well as acute myeloid leukemia (AML), B-lymphoblastic leukemia (B-ALL) and rarely T-lymphoblastic lymphoma/leukemia; see Table 1. Characteristics of reported myeloid and lymphoid neoplasms with BCR–JAK2 fusions[3]. Patients variably present with eosinophilia, and splenomegaly is a common clinical finding[1].
The clinical course of JAK2-rearranged patients resembles other patients with leukemias associated with other tyrosine kinase fusion genes, such as BCR-ABL1 positive CML. However, the clinical course can be more aggressive, with patients in chronic phase disease quickly progressing to AML[2][5].
Sites of Involvement
Peripheral blood and bone marrow
Morphologic Features
This 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)
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Prevalence |
|---|---|---|
| t(9;22)(p24.1;p11.2) | BCR-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[6].
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[7].
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 BCR-JAK2 fusions, and FISH analyses of BCR/ABL1, PDGFRA, PDGFRB, FGFR1, JAK2 gene regions can be used[3].
It is also important to distinguish BCR-JAK2 from the classical BCR-ABL1 positive CML, as the former entity may be resistant to imatinib therapy[3].
Diagnostic algorithm for hypereosinophilia, including eosinophilia-associated neoplasms[2].
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
Most patients present with MDS/MPN neoplasms with a more aggressive clinical course and variable sensitivity to current tyrosine kinase (TK) inhibitors. With this being such a rare entity and such variable presentation, there is no precise treatment option for BCR-JAK2 fusion[5]. Survival is highly variable and can range from days to years[1]. Some cases demonstrate a promising initial clinical response to TK inhibitors, but this is short-lived and long-term disease-free survival may only be achieved by allogeneic hematopoietic stem cell transplantation (AHSCT). Thus, TK inhibitors may be limited in their therapeutic value as solely bridging therapy before stem cell transplant can be performed[2][3].
Familial Forms
No familial forms have been documented.
Other Information
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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 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 2.4 Gotlib, Jason; et al. (2017). "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 3.5 He, Rong; et al. (2016-05). "BCR–JAK2 fusion in a myeloproliferative neoplasm with associated eosinophilia". Cancer Genetics. 209 (5): 223–228. doi:10.1016/j.cancergen.2016.03.002. ISSN 2210-7762. Check date values in:
|date=(help) - ↑ 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) - ↑ 5.0 5.1 Kantarcioglu, Bulent; et al. (2015). "Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature". International Journal of Hematology. 102 (3): 383–387. doi:10.1007/s12185-015-1792-2. ISSN 0925-5710.
- ↑ 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.
Notes
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