Poster Presentation 25th Lorne Cancer Conference 2013

Combined targeting of JAK2 and Bcl-2/Bcl-xL as a novel, potentially curative treatment for haematological malignancies expressing mutant JAK2 (#392)

Michaela Waibel 1 , Vanessa S Solomon 1 , Rachael A Ralli 1 , Sang-Kyu Kim 1 , Kellie-Marie Banks 1 , Eva Vidacs 1 , Ross A Dickins 2 , Jacques Ghysdael 3 , Mark A Dawson 4 , Richard B Lock 5 , Charles G Mullighan 6 , Ricky W Johnstone 1
  1. Peter MacCallum Cancer Centre, East Melbourne, Vic, Australia
  2. Walter and Elisa Hall Institute, Melbourne, Australia
  3. Institute Curie, Orsay, France
  4. University of Cambridge, Cambridge, UK
  5. Children’s Cancer Institute Australia for Medical Research, Sydney, Australia
  6. St. Jude Children’s Research Hospital, Memphis, USA

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.