Though relatively rare and likely under-diagnosed, the BCR-JAK2 fusion event in this case with CML/MPD adds to the spectrum of rare yet recurrent translocation partners for each of the genes, respectively. The BCR gene harbors two common breakpoints involved in the formation of the two alternative forms of the Philadelphia chromosome translocation seen in chronic myeloid leukemia and acute lymphoblastic leukemia ‐. These alternative breakpoints result in fusion of different exon sets of BCR to a common subset of the exons of the ABL1 gene located on chromosome 9 [p210(BCR-ABL) and p190(BCR-ABL)] with constitutive activation of ABL tyrosine kinase.
JAK2 kinase is a member of a family of non-receptor tyrosine kinases involved in non-catalytic cytokine receptor signaling. The common gain-of-function mutation, V617F, has been strongly associated with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Rare translocations involving JAK2 and resulting in fusion transcripts with oncogenic potential have been described in ALL and CML. Interestingly, the Drosophila Janus Kinase homolog, hopscotch (hop) gene, influences proliferation and differentiation of various cell types, particularly in hematopoietic lineages; mutations in the Drosophila hopscotch (hop) gene also cause proliferative defects .
These data provide evidence in support of a leukemogenic role for BCR-JAK2 fusion in myeloproliferative disorders, including CML, and complements data provided by the first case report by Griesinger et al. . To our knowledge this represents the second case of CML-like MPD with a translocation resulting in BCR-JAK2 fusion. Interestingly, this case may also suggest the potential recurrent nature of the chromosomal breakpoints and resulting in fusion between JAK2 and BCR genes. Breaks and fusions between the serine/threonine kinase BCR gene and tyrosine kinase JAK2 result in a fusion gene with a potential for constitutive kinase activity . This is accompanied by disruption of the normal functions of the individual counterparts. Fusion of the oligomerization domain of BCR with the crucial tyrosine kinase domain of JAK2 could be predicted to possess significant oncogenic potential. The N-terminal oligomerization domain of BCR is essential for the oncogenicity of the Bcr-Abl protein. Though speculative, it may be reasonable to predict that an intact tyrosine kinase domain of JAK2, under the influence of the BCR oligomerization domain, would lead to phosphorylation and constitutive activity of JAK2 kinase activity and downstream oncogenic effects. Similar speculative predictions have been proposed for oncogenic ETV6-JAK2 fusion [4, 10]. The impact of tyrosine kinase inhibitor (TKI) therapy in cases with JAK2 mutations and translocations is still unclear and likely ineffective in the few cases reported with translocations. However, in this case, Imatinib therapy was initiated during the second encounter (two years post-diagnosis). Loss to follow-up for the following five years precludes any conclusions regarding the effect, or lack thereof, of Imatinib in this patient.
This report, complemented by data from previous cases, strongly suggests shared pathways between JAK2 activation and oncogenic events resulting in ALL, CML and probably additional lympho- and myeloproliferative disorders. This makes it imperative to utilize multiple diagnostic tools (chromosomes, FISH, etc.,) to adequately investigate hematologic malignancies. Identification of additional cases will provide the opportunity to draw more explicit genotype-phenotype correlations and implement beneficial therapeutic regimens.