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Published online on July 29, 2004, 10.1073/pnas.0404432101
PNAS | August 10, 2004 | vol. 101 | no. 32 | 11755-11760


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MEDICAL SCIENCES
MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias

George Adrian Calin * {dagger}, Chang-Gong Liu * {dagger}, Cinzia Sevignani *, Manuela Ferracin {ddagger}, Nadia Felli *, §, Calin Dan Dumitru *, Masayoshi Shimizu *, Amelia Cimmino *, Simona Zupo ¶, Mariella Dono ||, Marie L. Dell'Aquila **, Hansjuerg Alder *, Laura Rassenti **, {dagger}{dagger}, Thomas J. Kipps **, {dagger}{dagger}, Florencia Bullrich *, {dagger}{dagger}, Massimo Negrini * {dagger}, and Carlo M. Croce *, {dagger}{dagger}, {ddagger}{ddagger}

*Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; {ddagger}Department of Experimental and Diagnostic Medicine and Interdepartment Center for Cancer Research, University of Ferrara, 44700 Ferrara, Italy; §Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore Sanita, 00161 Rome, Italy; Diagnostics of Lymphoproliferative Diseases, National Institute of Cancer, 16123 Genoa, Italy; ||Laboratorio di Analisi Cliniche, Ospedale Civile La Spezia, 19126 La Spezia, Italy; **Department of Medicine, University of California at San Diego, La Jolla, CA 92093; and {dagger}{dagger}Chronic Lymphocytic Leukemia Research Consortium, University of California at San Diego, La Jolla, CA 92093-0675

Contributed by Carlo M. Croce, June 21, 2004

Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673–676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253–258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia.

Abbreviations: miRNA, microRNA; CLL, chronic lymphocytic leukemia; MNC, mononuclear cells.

{dagger} G.A.C. and C.-G.L. contributed equally to this work.

{ddagger}{ddagger} To whom correspondence should be addressed. E-mail: c_croce{at}mail.jci.tju.edu.

© 2004 by The National Academy of Sciences of the USA


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