Constitutive activation of the JAK2 tyrosine kinase by gain-of-function mutations (eg JAK2V617F or JAK2R683G) or translocations leading to expression of JAK2 fusion proteins (eg TEL-JAK2) are frequently detected in myeloproliferative neoplasms (MPNs) and T- and pre-B cell acute lymphoblastic leukemias (T- and B-ALLs). With a view to designing novel rational therapies we examined the functional importance of various signaling pathways activated by oncogenic JAK2.
In primary T-ALLs derived from EµTEL-JAK2 transgenic mice, we found constitutive activation of STATs1, 3 and 5, the PI3K and MEK/ERK pathways, and a strong JAK2-driven expression of the pro-survival Bcl-2 family proteins Bcl-2 and Bcl-xL. Importantly, tumors expressing mutant JAK2 were exquisitely sensitive to the small molecule Bcl-2/Bcl-xL inhibitor ABT-737, while PI3K or MEK/ERK inhibitors had little or no effect on cell survival. Treatment of primary TEL-JAK2 T-ALL cells or JAK2-mutant pre-B-ALL cells with ABT-737 caused rapid induction of apoptosis in vitro and in vivo. ABT-737 sensitized TEL-JAK2 T-ALL tumors to treatment with conventional chemotherapeutic drugs such as cyclophosphamide and etoposide. However, the most robust anti-tumor response was achieved by combining ABT-737 with the JAK2 inhibitor TG101209. Treatment of mice bearing established TEL-JAK2 T-ALL tumors was well-tolerated and resulted in prolonged disease regressions and cures. Furthermore, this combination was also effective against xenotransplanted human JAK2-mutant precursor B cell ALLs grown in NOD/Scid IL-2Rγ-/- mice. Our studies provide strong support for the notion that targeting the JAK2 signaling network at two nodal points – at the initiating stage (activated JAK2) and at a key effector stage (Bcl-2/Bcl-xL) - provides the greatest therapeutic benefit. Our results therefore provide a strong rational for combining ABT-737 and small molecule JAK2 inhibitors for the treatment of hematological malignancies driven by mutant JAK2.