Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon ? specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells.

ABSTRACT: Polycythemia vera (PV) treatment with interferon ? (IFN?) is frequently limited by dose-related toxicity. PV CD34(+) cells are characterized by overexpression of Bcl-xL, which can be antagonized by ABT-737 leading to apoptosis. We explored the effects of ABT-737 and IFN? on PV hematopoiesis. Both IFN? 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 IFN? and ABT-737 in combination resulted in the reduction of the proportion of JAK2V617F(+) colonies similar to that observed with higher doses of IFN?. These data provide the rationale for combination therapy with low doses of IFN? and a BH3 mimetic for patients with PV.

SUBMITTER: Lu M 

PROVIDER: S-EPMC2993627 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature