Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias

Leukemia. 2007 Sep;21(9):2000-9. doi: 10.1038/sj.leu.2404808. Epub 2007 Jun 28.

Abstract

Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.

Publication types

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

MeSH terms

  • Acute Disease
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Leukemic*
  • Gene Rearrangement
  • Histone-Lysine N-Methyltransferase
  • Homeobox A10 Proteins
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Leukemia, Myeloid / genetics*
  • Male
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Transcription Factors / genetics

Substances

  • HOXB2 protein, human
  • HOXB6 protein, human
  • Homeobox A10 Proteins
  • Homeodomain Proteins
  • KMT2A protein, human
  • MEIS1 protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Transcription Factors
  • homeobox protein HOXA9
  • nucleophosmin
  • HOXA10 protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase