title: Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.
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.
authors.affiliation: 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.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Rooha
authors.initials: R
authors.lastname: Contractor
authors.forename: Twee
authors.initials: T
authors.lastname: Tsao
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
authors.forename: Dayong
authors.initials: D
authors.lastname: Zhai
authors.forename: Yue-Xi
authors.initials: YX
authors.lastname: Shi
authors.forename: Thomas
authors.initials: T
authors.lastname: Sneed
authors.forename: Monique
authors.initials: M
authors.lastname: Verhaegen
authors.forename: Maria
authors.initials: M
authors.lastname: Soengas
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.forename: Teresa
authors.initials: T
authors.lastname: McQueen
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Schober
authors.forename: Julie C
authors.initials: JC
authors.lastname: Watt
authors.forename: Tilahun
authors.initials: T
authors.lastname: Jiffar
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Ling
authors.forename: Frank C
authors.initials: FC
authors.lastname: Marini
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: Martin
authors.initials: M
authors.lastname: Dietrich
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.forename: W Stratford
authors.initials: WS
authors.lastname: May
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001713:Biphenyl Compounds / Q000378:metabolism / Q000627:therapeutic use; D002460:Cell Line; D019281:Dimerization; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism / Q000627:therapeutic use; D010879:Piperazines / Q000378:metabolism / Q000627:therapeutic use; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism / Q000627:therapeutic use; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein