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

Blood
Min LuRonald Hoffman

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.

References

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Citations

Aug 8, 2012·Oncogene·W Vainchenker, S N Constantinescu
Dec 14, 2011·Hematology·Alessandro M Vannucchi
Feb 9, 2011·Leukemia & Lymphoma·Nicholas J Donato, Luke F Peterson
Jan 18, 2011·Current Opinion in Immunology·Cameron J Turtle, Stanley R Riddell
Dec 10, 2014·Clinical Lymphoma, Myeloma & Leukemia·Florence PasquierWilliam Vainchenker
Apr 23, 2013·Therapeutic Advances in Hematology·Claire Harrison, Alessandro M Vannucchi
Mar 9, 2018·Expert Review of Hematology·Patrick M Harrington, Claire N Harrison
May 1, 2021·Cells·Douglas Tremblay, John Mascarenhas

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