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Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a  BCR-JAK2  fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence  in situ  hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a  BCR-JAK2  fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR.  BCR-JAK2  codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain.  In vitro  analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying  BCR-JAK2  induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where  Bcl-xL  gene expression was elicited. Primary mouse progenitor cells transduced with  BCR-JAK2  also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased  Bcl-xL  expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2  in vivo . Together these findings suggest that adult and pediatric patients with  BCR-ABL -negative leukemia and  JAK2  overexpression may benefit from targeted therapies.

Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase