Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations

Leukemia. 2006 Apr;20(4):635-44. doi: 10.1038/sj.leu.2404136.


AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML). Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We analyzed gene alterations in MDS/AML patients with AML1 mutations, comparing them to alterations in those without an AML1 mutation. AML1 mutations were significantly associated with -7/7q-, whereas MDS/AML patients without AML1 mutations showed a high frequency of -5/5q- and a complex karyotype. Patients with AML1 mutations showed more mutations of their FLT3, N-RAS, PTPN11, and NF1 genes, resulting in a significantly higher mutation frequency for receptor tyrosine kinase (RTK)-RAS signaling pathways in AML1-mutated MDS/AML patients compared to AML1-wild-type MDS/AML patients (38% versus 6.3%, P < 0.0001). Conversely, p53 mutations were detected only in patients without AML1 mutations. Furthermore, blast cells of the AML1-mutated patients expressing surface c-KIT, and SHP-2 mutants contributed to prolonged and enhanced extracellular signal-regulated kinase activation following stem cell factor stimulation. Our results suggest that MDS/AML arising from AML1/RUNX1 mutations has a significant association with -7/7q- alteration, and frequently involves RTK-RAS signaling pathway activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Chromosome Aberrations
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Cytogenetic Analysis
  • DNA Mutational Analysis / methods
  • Epidermal Growth Factor / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genes, ras*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Ligands
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism*
  • Point Mutation*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / genetics
  • Sensitivity and Specificity
  • Signal Transduction*
  • Tumor Cells, Cultured


  • Core Binding Factor Alpha 2 Subunit
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • RUNX1 protein, human
  • Epidermal Growth Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases