Survivin is highly expressed in CD34+38− leukemic stem/progenitor cells and predicts poor clinical outcomes in AML

• Published in: Blood 2012-07, Vol.120 (1), p.173-180
• Main Authors: Carter, Bing Z., Qiu, Yihua, Huang, Xuelin, Diao, Lixia, Zhang, Nianxiang, Coombes, Kevin R., Mak, Duncan H., Konopleva, Marina, Cortes, Jorge, Kantarjian, Hagop M., Mills, Gordon B., Andreeff, Michael, Kornblau, Steven M.
• Format: Article
• Language: English
• Subjects: Adolescent; ADP-ribosyl Cyclase 1 - metabolism; Adult; Aged; Aged, 80 and over; Antigens, CD34 - metabolism; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cell Proliferation; Cell Survival - physiology; Drug Resistance, Neoplasm - physiology; Female; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - physiology; Humans; Inhibitor of Apoptosis Proteins - metabolism; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Membrane Glycoproteins - metabolism; Middle Aged; Myeloid Neoplasia; Predictive Value of Tests; Protein Array Analysis; Survival Analysis; Survivin; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-02-409888

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.