Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia.
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.
Konopleva
Marina
M
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.
Contractor
Rooha
R
Tsao
Twee
T
Samudio
Ismael
I
Ruvolo
Peter P
PP
Kitada
Shinichi
S
Deng
Xingming
X
Zhai
Dayong
D
Shi
Yue-Xi
YX
Sneed
Thomas
T
Verhaegen
Monique
M
Soengas
Maria
M
Ruvolo
Vivian R
VR
McQueen
Teresa
T
Schober
Wendy D
WD
Watt
Julie C
JC
Jiffar
Tilahun
T
Ling
Xiaoyang
X
Marini
Frank C
FC
Harris
David
D
Dietrich
Martin
M
Estrov
Zeev
Z
McCubrey
James
J
May
W Stratford
WS
Reed
John C
JC
Andreeff
Michael
M
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
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