Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias

BMC Cancer. 2010 Aug 2:10:401. doi: 10.1186/1471-2407-10-401.


Background: Gene mutation is an important mechanism of myeloid leukemogenesis. However, the number and combination of gene mutated in myeloid malignancies is still a matter of investigation.

Methods: We searched for mutations in the ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in 65 myelodysplastic syndromes (MDSs) and 64 acute myeloid leukemias (AMLs) without balanced translocation or complex karyotype.

Results: Mutations in ASXL1 and CBL were frequent in refractory anemia with excess of blasts. Mutations in TET2 occurred with similar frequency in MDSs and AMLs and associated equally with either ASXL1 or NPM1 mutations. Mutations of RUNX1 were mutually exclusive with TET2 and combined with ASXL1 but not with NPM1. Mutations in FLT3 (mutation and internal tandem duplication), IDH1, IDH2, NPM1 and WT1 occurred primarily in AMLs.

Conclusion: Only 14% MDSs but half AMLs had at least two mutations in the genes studied. Based on the observed combinations and exclusions we classified the 12 genes into four classes and propose a highly speculative model that at least a mutation in one of each class is necessary for developing AML with simple or normal karyotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Core Binding Factor Alpha 2 Subunit / genetics
  • DNA, Neoplasm / genetics
  • DNA-Binding Proteins / genetics
  • Dioxygenases
  • Female
  • Genes, ras / physiology
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Janus Kinase 2 / genetics
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / pathology
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins / genetics
  • Nucleophosmin
  • Polymerase Chain Reaction
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Repressor Proteins / genetics
  • WT1 Proteins / genetics
  • fms-Like Tyrosine Kinase 3 / genetics
  • ras Proteins / genetics


  • ASXL1 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • KRAS protein, human
  • NPM1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RUNX1 protein, human
  • Repressor Proteins
  • WT1 Proteins
  • Nucleophosmin
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Dioxygenases
  • TET2 protein, human
  • Proto-Oncogene Proteins c-cbl
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • JAK2 protein, human
  • Janus Kinase 2
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • CBL protein, human