Expression of ARC (apoptosis repressor with caspase recruitment domain), an antiapoptotic protein, is strongly prognostic in AML.
Regulators of apoptosis in acute myeloid leukemia (AML) have been extensively studied and are considered excellent therapeutic targets. Apoptosis repressor with caspase recruitment domain (ARC), an antiapoptotic protein originally found to be involved in apoptosis of cardiac cells, was recently demonstrated to be overexpressed in several solid tumors. To assess its importance in AML, we profiled ARC expression in 511 newly diagnosed AML patients using a validated robust reverse-phase protein array and correlated ARC levels with clinical outcomes. ARC was variably expressed in samples from patients with AML. ARC level was not associated with cytogenetic groups or with FLT-3 mutation status. However, patients with low or medium ARC protein levels had significantly better outcomes than those with high ARC levels: longer overall survival (median, 53.9 or 61.6 vs 38.9 weeks, P = .0015) and longer remission duration (median, 97.6 or 44.7 vs 31.1 weeks, P = .0007). Multivariate analysis indicated that ARC was a statistically significant independent predictor of survival in AML (P = .00013). Inhibition of ARC promoted apoptosis and sensitized cytosine arabinoside-induced apoptosis in OCI-AML3 cells. These results suggest that ARC expression levels are highly prognostic in AML and that ARC is a potential therapeutic target in AML.
Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Bing Z
BZ
Carter
Yi Hua
YH
Qiu
Nianxiang
N
Zhang
Kevin R
KR
Coombes
Duncan H
DH
Mak
Deborah A
DA
Thomas
Farhad
F
Ravandi
Hagop M
HM
Kantarjian
Erich
E
Koller
Michael
M
Andreeff
Steven M
SM
Kornblau
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; D016376:Oligonucleotides, Antisense; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3