Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia

Oncogene. 2004 May 24;23(24):4284-96. doi: 10.1038/sj.onc.1207779.


The RUNX1/AML1 gene is the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as another mode of genetic alteration in development of leukemia. Monoallelic germline mutations in RUNX1 result in familial platelet disorder predisposed to acute myelogenous leukemia (FPD/AML). Sporadic point mutations are frequently found in three leukemia entities: AML M0 subtype, MDS-AML, and secondary (therapy-related) MDS/AML. Therapy-related leukemias resulting from anticancer treatments are not uncommon, and the incidence of RUNX1 point mutations appears comparable to the incidence of the t(8;21) AML M2 subtype and the inv(16) AML M4Eo subtype. Half of the point mutations in M0 cases are biallelic, although the frequency varies with ethnicity. Most of the RUNX1 mutations are clustered in the Runt domain and result in defective DNA binding but active beta-subunit binding, which is consistent with three-dimensional structural findings and may explain the dominant inhibitory effects. Unlike the classical tumor suppressor genes requiring biallelic inactivation, haploinsufficient RUNX1 is apparently leukemogenic. However, RUNX1 abnormalities per se are insufficient to cause full-blown leukemia. Intensive investigation of cooperating genetic alterations should elucidate leukemic mechanisms.

Publication types

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

MeSH terms

  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Frequency
  • Genes, Dominant
  • Humans
  • Leukemia / etiology
  • Leukemia / genetics*
  • Phenotype
  • Point Mutation*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RUNX1 protein, human
  • Transcription Factors