2. Academic Validation
  3. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia

  • Cancer Cell. 2006 Nov;10(5):375-88. doi: 10.1016/j.ccr.2006.10.006.
Marina Konopleva 1,  Rooha Contractor,  Twee Tsao,  Ismael Samudio,  Peter P Ruvolo,  Shinichi Kitada,  Xingming Deng,  Dayong Zhai,  Yue-Xi Shi,  Thomas Sneed,  Monique Verhaegen,  Maria Soengas,  Vivian R Ruvolo,  Teresa McQueen,  Wendy D Schober,  Julie C Watt,  Tilahun Jiffar,  Xiaoyang Ling,  Frank C Marini,  David Harris,  Martin Dietrich,  Zeev Estrov,  James McCubrey,  W Stratford May,  John C Reed,  Michael Andreeff
Affiliations

Affiliation

  • 1 Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
PMID: 17097560 DOI: 10.1016/j.ccr.2006.10.006
Abstract

Bcl-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung Cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the Bcl-2/Bax complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated Bcl-2 or increased Mcl-1, ABT-737 was inactive. Inhibition of Bcl-2 phosphorylation and reduction of Mcl-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.

Figures
Products