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Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (10), p.3945-3950
Main Authors: Garzon, Ramiro, Garofalo, Michela, Martelli, Maria Paola, Briesewitz, Roger, Wang, Lisheng, Fernandez-Cymering, Cecilia, Volinia, Stefano, Liu, Chang-Gong, Schnittger, Susanne, Haferlach, Torsten, Liso, Arcangelo, Diverio, Daniela, Mancini, Marco, Meloni, Giovanna, Foa, Robin, Martelli, Massimo F, Mecucci, Cristina, Croce, Carlo M, Falini, Brunangelo
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Language:English
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.0800135105