Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles

EMBO J. 2007 Feb 21;26(4):1163-75. doi: 10.1038/sj.emboj.7601568. Epub 2007 Feb 8.


Monoallelic RUNX1 mutations cause familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML). Sporadic mono- and biallelic mutations are found at high frequencies in AML M0, in radiation-associated and therapy-related myelodysplastic syndrome and AML, and in isolated cases of AML M2, M5a, M3 relapse, and chronic myelogenous leukemia in blast phase. Mutations in RUNX2 cause the inherited skeletal disorder cleidocranial dysplasia (CCD). Most hematopoietic missense mutations in Runx1 involve DNA-contacting residues in the Runt domain, whereas the majority of CCD mutations in Runx2 are predicted to impair CBFbeta binding or the Runt domain structure. We introduced different classes of missense mutations into Runx1 and characterized their effects on DNA and CBFbeta binding by the Runt domain, and on Runx1 function in vivo. Mutations involving DNA-contacting residues severely inactivate Runx1 function, whereas mutations that affect CBFbeta binding but not DNA binding result in hypomorphic alleles. We conclude that hypomorphic RUNX2 alleles can cause CCD, whereas hematopoietic disease requires more severely inactivating RUNX1 mutations.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Cell Count
  • Blotting, Western
  • Cleidocranial Dysplasia / genetics*
  • Core Binding Factor Alpha 1 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor beta Subunit / metabolism
  • DNA / metabolism*
  • DNA Primers
  • Flow Cytometry
  • Fluorescence Resonance Energy Transfer
  • Hematologic Diseases / genetics*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular*
  • Mutation, Missense / genetics*
  • Protein Structure, Tertiary*
  • Spectrometry, Fluorescence
  • Two-Hybrid System Techniques


  • Cbfb protein, mouse
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor beta Subunit
  • DNA Primers
  • DNA