Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin

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 upregulation observed in NPMc؉ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD؉ samples were characterized by upregulation 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. FLT3-ITD ͉ HOX ͉ NPM1A cute myeloid leukemia (AML) arises from multiple and sequential genetic alterations involving hematopoietic precursors (1). In Ϸ25% of cases, specific chromosomal translocations like the t(8;21), inv(16) or t(15;17) represent the initial events leading to malignant transformation (1) and are associated with a good outcome. In contrast, 40-50% of AMLs have normal karyotype by conventional banding analysis and are characterized by great molecular and clinical heterogeneity (2). Recent work has identified novel molecular abnormalities in normal karyotype AML (NK-AML) that has improved the classification and risk stratification of this large subgroup of patients. Among them, internal tandem duplications in the juxta-membrane domain or mutations in the second tyrosine kinase domain (TKD) of the FLT3 gene have been found in 30-45% of NK-AML (3). Both types of mutations constitutively activate FLT3 and FLT3-ITD mutations have been associated with increased risk of relapse (4). Mutations in the myeloid transcription factor CEBPA have been detected in 10-15% of NK-AML (5) and are associated with favorable prognosis (5, 6).Mutations of the nucleophosmin (NPM1) gene, usually occurring at exon-12 (7) and more rarely at exon-11 (8) represent the most common genetic alteration in AML-NK (50-60% of cases) and account for about one-third of all adult AML (7). This gene encodes for a ubiquitously expressed...

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