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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3183-3189.
Prepublished online as a Blood First Edition Paper on January 10, 2008; DOI 10.1182/blood-2007-07-098749.
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Submitted July 2, 2007
Accepted December 30, 2007
MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia
Ramiro Garzon, Stefano Volinia, Chang-Gong Liu, Cecilia Fernandez-Cymering, Tiziana Palumbo, Flavia Pichiorri, Muller Fabbri, Kevin Coombes, Hansjuerg Alder, Tatsuya Nakamura, Neal Flomenberg, Guido Marcucci, George A. Calin, Steven M. Kornblau, Hagop Kantarjian, Clara D. Bloomfield, Michael Andreeff, and Carlo M. Croce*
Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
DAMA, Data Mining of DNA Microarrays, University of Ferrara, Ferrara, Italy
Depament of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
Biostatistics Division, MD Anderson Cancer Center, Texas State University, Houston, TX, United States
Department of Medicine, The Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Texas State University, Houston, TX, United States
Department of Blood and Bone Marrow Transplantation, MD Anderson Cancer Center, Texas State University, Houston, TX, United States
Department of Leukemia, MD Anderson Cancer Center, Texas State University, Houston, TX, United States
* Corresponding author; email: carlo.croce{at}osumc.edu.
MicroRNAs (miRNAs) are small RNAs of 19-25 nucleotides that are negative regulators of gene expression. To determine whether miRNAs are associated with cytogenetic abnormalities and clinical features in acute myeloid leukemia (AML), we evaluated the miRNA expression of CD34+ cells and 122 untreated adult AML cases using a microarray platform. After background subtraction and normalization using a set of housekeeping genes, data were analyzed using Significance Analysis of Microarrays. An independent set of 60 untreated AML patients was used to validate the outcome signatures using real time PCR. We identified several miRNAs differentially expressed between CD34+ normal cells and the AML samples. MiRNA expression was also closely associated with selected cytogenetic and molecular abnormalities like t(11q23), isolated trisomy 8 and FLT3-ITD mutations. Furthermore, patients with high expression of miR-191 and miR-199a had significantly worse overall and event free survival than AML patients with low expression (Overall survival: miR-191 P=0.03 and miR-199a P=0.0006, Cox regression). In conclusion, miRNA expression in AML is closely associated with cytogenetics and FLT3-ITD mutations. A small subset of miRNAs is correlated with survival.
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