Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Substitution / genetics*
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Antigens, CD34 / metabolism
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Biphenyl Compounds / pharmacology*
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Biphenyl Compounds / therapeutic use
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / pathology
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Colony-Forming Units Assay
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Drug Synergism
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Fetal Blood / cytology
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / enzymology
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Humans
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Interferon alpha-2
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Interferon-alpha / pharmacology*
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Janus Kinase 2 / genetics*
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Janus Kinase 2 / metabolism
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Nitrophenols / pharmacology*
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Nitrophenols / therapeutic use
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Polycythemia Vera / drug therapy
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Polycythemia Vera / enzymology*
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Polycythemia Vera / pathology
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Polyethylene Glycols / pharmacology*
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Recombinant Proteins
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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bcl-X Protein / antagonists & inhibitors*
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bcl-X Protein / metabolism
Substances
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ABT-737
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Antigens, CD34
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Biphenyl Compounds
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Interferon alpha-2
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Interferon-alpha
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Nitrophenols
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Piperazines
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Recombinant Proteins
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Sulfonamides
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bcl-X Protein
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Polyethylene Glycols
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JAK2 protein, human
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Janus Kinase 2
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peginterferon alfa-2a