Blood Journal
Leading the way in experimental and clinical research in hematology

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

  1. Xinghui Zhao1,2,
  2. Aili Chen1,3,4,
  3. Xiaomei Yan1,
  4. Yue Zhang1,5,
  5. Fuhong He3,
  6. Yoshihiro Hayashi1,
  7. Yunzhu Dong2,
  8. Yalan Rao1,
  9. Bo Li1,3,4,
  10. Rajeana M. Conway1,
  11. Alba Maiques-Diaz6,
  12. Shannon E. Elf7,
  13. Nuomin Huang1,
  14. Johannes Zuber8,
  15. Zhijian Xiao5,
  16. William Tse9,
  17. Daniel G. Tenen10,11,
  18. Qianfei Wang3,
  19. Wei Chen2,
  20. James C. Mulloy1,
  21. Stephen D. Nimer7,12, and
  22. Gang Huang1,2
  1. 1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
  2. 2Laboratory of Vaccine and Antibody Engineering, Beijing Institute of Biotechnology, Beijing, People’s Republic of China;
  3. 3Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;
  4. 4University of Chinese Academy of Sciences, Beijing, China;
  5. 5State Key Laboratory of Experiment Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China;
  6. 6Molecular Cytogenetics Group, Human Cancer Genetics programme, Spanish National Cancer Research Centre, Madrid, Spain;
  7. 7Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY;
  8. 8Research Institute of Molecular Pathology, Vienna, Austria;
  9. 9Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV;
  10. 10Harvard Stem Cell Institute, Harvard Medical School, Boston, MA;
  11. 11Cancer Science Institute, National University of Singapore, Singapore; and
  12. 12Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL

Key Points

  • MLL oncoproteins downregulate RUNX1/CBFβ by the CXXC domain and flanking region as a critical step in the development of MLL-related leukemias.

Abstract

RUNX1/CBFβ (core binding factor [CBF]) is a heterodimeric transcription factor complex that is frequently involved in chromosomal translocations, point mutations, or deletions in acute leukemia. The mixed lineage leukemia (MLL) gene is also frequently involved in chromosomal translocations or partial tandem duplication in acute leukemia. The MLL protein interacts with RUNX1 and prevents RUNX1 from ubiquitin-mediated degradation. RUNX1/CBFβ recruits MLL to regulate downstream target genes. However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We confirmed this finding in Mll-Af9 knock-in mice and human M4/M5 acute myeloid leukemia (AML) cell lines, with or without MLL translocations, showing that MLL translocations cause a hypomorph phenotype of RUNX1/CBFβ. Overexpression of RUNX1 inhibits the development of AML in Mll-Af9 knock-in mice; conversely, further reducing Runx1/Cbfβ levels accelerates MLL-AF9–mediated AML in bone marrow transplantation assays. These data reveal a newly defined negative regulation of RUNX1/CBFβ by MLL fusion proteins and suggest that targeting RUNX1/CBFβ levels may be a potential therapy for MLLs.

  • Submitted March 11, 2013.
  • Accepted January 13, 2014.
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