Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin

Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3945-50. doi: 10.1073/pnas.0800135105. Epub 2008 Feb 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD34 / metabolism
  • Cell Line, Tumor
  • Cluster Analysis
  • Cytoplasm / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Homeobox A10 Proteins
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • MicroRNAs / genetics*
  • Mutant Proteins / genetics*
  • Mutation / genetics*
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Antigens, CD34
  • HOXB4 protein, human
  • Homeobox A10 Proteins
  • Homeodomain Proteins
  • MEIS1 protein, human
  • MicroRNAs
  • Mutant Proteins
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Transcription Factors
  • nucleophosmin
  • HOXA10 protein, human
  • fms-Like Tyrosine Kinase 3