Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon α specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells.
Polycythemia vera (PV) treatment with interferon α (IFNα) 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 IFNα on PV hematopoiesis. Both IFNα 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 IFNα and ABT-737 in combination resulted in the reduction of the proportion of JAK2V617F(+) colonies similar to that observed with higher doses of IFNα. These data provide the rationale for combination therapy with low doses of IFNα and a BH3 mimetic for patients with PV.
Lu
Min
M
Tisch Cancer Institute and Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Wang
Jiapeng
J
Li
Yan
Y
Berenzon
Dmitriy
D
Wang
Xiaoli
X
Mascarenhas
John
J
Xu
Mingjiang
M
Hoffman
Ronald
R
D019943:Amino Acid Substitution / Q000235:genetics*; D018952:Antigens, CD34 / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D003114:Colony-Forming Units Assay; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011087:Polycythemia Vera / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
C501332:ABT-737; D018952:Antigens, CD34; D001713:Biphenyl Compounds; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009596:Nitrophenols; D010879:Piperazines; D011994:Recombinant Proteins; D013449:Sulfonamides; D051020:bcl-X Protein; D011092:Polyethylene Glycols; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C100416:peginterferon alfa-2a