Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon {alpha} specifically targets JAK2V617F positive polycythemia vera hematopoietic progenitor cells.
Blood 2010 Jul 12; In press
Lu M, Wang J, Li Y, Berenzon D, Wang X, Mascarenhas J, Xu M, Hoffman R
Tisch Cancer Institute and Department of Medicine, Mount Sinai School of Medicine, New York, NY, United States.
Polycythemia vera (PV) treatment with interferon alpha (IFNalpha), is frequently limited by dose related toxicity. PV CD34(+) are characterized by over expression of Bcl-xL which can be antagonized by ABT-737 leading to apoptosis. We explored the effects of ABT-737 and IFNalpha on PV hematopoiesis. Both IFNalpha and ABT-737 alone or in combination had a modest effect on normal hematopoiesis but each individually were able to markedly induce PV CD34(+) cell apoptosis and suppress hematopoietic colony formation. The inhibitory activities of these agents in combination were greater against PV hematopoiesis than either agent alone. The exposure of PV CD34(+) cells to low doses of IFNalpha and ABT-737 in combination resulted in the reduction of the proportion of JAK2V617F(+) colonies similar to that observed with higher doses of IFNalpha. These data provide the rationale for combination therapy with low doses of IFNalpha and a BH3 mimetic for patients with PV.
Keywords: ABT-737 Bcl-xL Polycythemia vera