Survivin is highly expressed in CD34(+)38(-) leukemic stem/progenitor cells and predicts poor clinical outcomes in AML.
Survivin, a member of the inhibitors of apoptosis protein family, plays important roles in cell proliferation and survival and is highly expressed in various malignancies, including leukemias. To better understand its role in acute myeloid leukemia (AML), we profiled survivin expression in samples obtained from 511 newly diagnosed AML patients and in CD34(+)38(-) AML stem/progenitor cells using a validated reverse-phase protein array; we correlated its levels with clinical outcomes and with levels of other proteins in the same sample set. We found that survivin levels were higher in bone marrow than in paired peripheral blood leukemic cells (n = 140, P = .0001) and that higher survivin levels significantly predicted shorter overall (P = .016) and event-free (P = .023) survival in multivariate Cox model analysis. Importantly, survivin levels were significantly higher in CD34(+)38(-) AML stem/progenitor cells than in bulk blasts and total CD34(+) AML cells (P < .05). Survivin expression correlated with the expressions of multiple proteins involved with cell proliferation and survival. Particularly, its expression strongly correlated with HIF1α in the stem/progenitor cell compartment. These results suggest that survivin is a prognostic biomarker in AML and that survivin, which is overexpressed in AML stem/progenitor cells, remains a potentially important target for leukemia therapy.
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. bicarter@mdanderson.org
Bing Z
BZ
Carter
Yihua
Y
Qiu
Xuelin
X
Huang
Lixia
L
Diao
Nianxiang
N
Zhang
Kevin R
KR
Coombes
Duncan H
DH
Mak
Marina
M
Konopleva
Jorge
J
Cortes
Hagop M
HM
Kantarjian
Gordon B
GB
Mills
Michael
M
Andreeff
Steven M
SM
Kornblau
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D011237:Predictive Value of Tests; D040081:Protein Array Analysis; D016019:Survival Analysis; D000077022:Survivin; D055815:Young Adult
D018952:Antigens, CD34; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D000077022:Survivin; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1