C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

Leukemia. 2012 Feb;26(2):303-11. doi: 10.1038/leu.2011.202. Epub 2011 Aug 12.


Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation(s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. γH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage(-)Sca1(+)c-kit(+) (LSK) cells than in mock-transduced LSK cells both in a steady state and after γ-ray treatment. Expression profiling by real-time -PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • DNA Damage*
  • DNA Repair*
  • Gene Expression Profiling
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Mutation*
  • Myelodysplastic Syndromes / genetics
  • Nuclear Proteins / genetics
  • Real-Time Polymerase Chain Reaction
  • Transcription, Genetic


  • Cell Cycle Proteins
  • Core Binding Factor Alpha 2 Subunit
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • RUNX1 protein, human