Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin

doi:10.1073/pnas.0800135105

Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin

Departments of *Medicine and
^†Molecular Virology and Human Genetics, Comprehensive Cancer Center, and
^§College of Pharmacology, Ohio State University, Columbus, OH 43221;
^‡Institute of Hematology, University of Perugia, 6100 Perugia, Italy;
^¶MLL Münchner Leukämie Labor GmbH, 85356 Munich, Germany;
^‖Institute of Hematology, University of Foggia, 71020 Foggia, Italy; and
**Institute of Hematology, University “La Sapienza,” 0185 Rome, Italy

Contributed by Carlo M. Croce, January 6, 2008 (received for review December 22, 2007)

Abstract

Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19–25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.

Footnotes

^††To whom correspondence should be addressed at:
Ohio State University, Comprehensive Cancer Center, BRT Building, Room 1082, 460 12th Avenue, Columbus, OH 43210.
E-mail: carlo.croce{at}osumc.edu
Author contributions: R.G. and M.G. contributed equally to this work; R.G., M.G., M.P.M., R.B., S.V., C.M.C., and B.F. designed research; R.G., M.G., M.P.M., R.B., L.W., C.-G.L., S.S., T.H., A.L., D.D., M.M., G.M., R.F., M.F.M., C.M., and B.F. performed research; S.S., T.H., A.L., D.D., M.M., R.F., M.F.M., C.M., and B.F. contributed new reagents/analytic tools; R.G., M.G., M.P.M., R.B., C.F.-C., S.V., S.S., T.H., A.L., D.D., M.M., M.F.M., C.M., C.M.C., and B.F. analyzed data; and R.G. and B.F. wrote the paper.
B.F. and C.M. have applied for a patent on clinical use of NPM1 mutants. The authors declare no other conflict of interest.
Data deposition: The microarray dataset has been deposited in the ArrayExpress database, www.ebi.ac.uk/arrayexpress (accession no. E-TABM-429).
This article contains supporting information online at www.pnas.org/cgi/content/full/0800135105/DC1.