BCR–JAK2 drives a myeloproliferative neoplasm in transplanted mice

Abstract

BCR-JAK2 is an infrequent gene fusion found in chronic/acute, myeloid/lymphoid Philadelphia chromosome-negative leukaemia. In this study, we demonstrated that in vivo expression of BCR-JAK2 in mice induces neoplasia, with fatal consequences. Transplantation of BCR-JAK2 bone marrow progenitors promoted splenomegaly, with megakaryocyte infiltration and elevated leukocytosis of myeloid origin. Analysis of peripheral blood revealed the presence of immature myeloid cells, platelet aggregates and ineffective erythropoiesis. A possible molecular mechanism for these observations involved inhibition of apoptosis by deregulated expression of the anti-apoptotic mediator Bcl-xL and the serine/threonine kinase Pim1. Together, these data provide a suitable in vivo molecular mechanism for leukaemia induction by BCR-JAK2 that validates the use of this model as a relevant preclinical tool for the design of new targeted therapies in Philadelphia chromosome-negative leukaemia involving BCR-JAK2-driven activation of the JAK2 pathway.

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

“…We therefore sought to evaluate the clinical characteristics and response to various TKI in 18 patients with myeloid neoplasms and associated PCM1‐JAK2 , BCR‐JAK2 or ETV6‐ABL1 fusion genes. In an extended analysis, we integrated our data into the reports of 40 patients with JAK2 fusion genes ( PCM1‐JAK2 , n = 28) 8,9,12‐15,28‐40 or BCR‐JAK2 (n = 12) 41‐52 and 14 patients with TKI‐treated ETV6‐ABL1 positive chronic myeloid neoplasms 16‐27,53,54 . This analysis provides a comprehensive overview of responses to TKIs in patients with these rare fusions.…”

The First Case Report of JAK2–BCR–PPP1R32 Fusion Genes Because of a Translocation (9;22;11)(p24;q11.2;q13) in a Patient With Myeloproliferative Neoplasm

“…The BCR-JAK2 fusion gene is rare but has been reported in cases of ALL, AML, MPN, and atypical CML, indicating that the BCR-JAK2 rearrangement lacks lineage specificity [3]. The BCR-JAK2 fusion gene triggers Stat5 phosphorylation and the expression of Stat5 target genes, such as the anti-apoptotic Bcl-xL gene, thereby promoting tumorigenic properties and improving cell survival [7]. JAK2 inhibitors may be effective against hematological tumors with BCR-JAK2 fusion genes, but the response may be transient or even ineffective [5].…”