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

Min Lu, Jiapeng Wang, Yan Li, Dmitriy Berenzon, Xiaoli Wang, John Mascarenhas, Mingjiang Xu, Ronald Hoffman

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4284-4287
Number of pages4
JournalBlood
Volume116
Issue number20
DOIs
StatePublished - Nov 18 2010
Externally publishedYes

Fingerprint

Polycythemia Vera
Hematopoietic Stem Cells
Interferons
Hematopoiesis
Therapeutics
Apoptosis
Toxicity
ABT-737

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon α specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells. / Lu, Min; Wang, Jiapeng; Li, Yan; Berenzon, Dmitriy; Wang, Xiaoli; Mascarenhas, John; Xu, Mingjiang; Hoffman, Ronald.

In: Blood, Vol. 116, No. 20, 18.11.2010, p. 4284-4287.

Research output: Contribution to journalArticle

Lu, Min ; Wang, Jiapeng ; Li, Yan ; Berenzon, Dmitriy ; Wang, Xiaoli ; Mascarenhas, John ; Xu, Mingjiang ; Hoffman, Ronald. / Treatment with the Bcl-xL inhibitor ABT-737 in combination with interferon α specifically targets JAK2V617F-positive polycythemia vera hematopoietic progenitor cells. In: Blood. 2010 ; Vol. 116, No. 20. pp. 4284-4287.
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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.",
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AU - Wang, Jiapeng

AU - Li, Yan

AU - Berenzon, Dmitriy

AU - Wang, Xiaoli

AU - Mascarenhas, John

AU - Xu, Mingjiang

AU - Hoffman, Ronald

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AB - 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.

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