A broad range of human leukemias carries RUNX1 and MLL genetic alterations. Despite such widespread involvements, the relationship between RUNX1 and MLL has never been appreciated. Recently, we showed that RUNX1 physically and functionally interacts with MLL, thereby regulating the epigenetic status of critical cis-regulatory elements for hematopoietic genes. This newly unveiled interaction between the two most prevalent leukemia genes has solved a long-standing conundrum: leukemia-associated RUNX1 N-terminal point mutants that exhibit no obvious functional abnormalities in classical assays for the assessment of transcriptional activities. These mutants turned out to be defective in MLL interaction and subsequent epigenetic modifications that can be examined by the histone-modification status of cis-regulatory elements in the target genes. RUNX1/MLL binding confirms the importance of RUNX1 function as an epigenetic regulator. Recent studies employing next-generation sequencing on human hematological malignancies identified a plethora of mutations in epigenetic regulator genes. These new findings would enhance our understanding on the mechanistic basis for leukemia development and may provide a novel direction for therapeutic applications.
CP Koh 1,6, CQ Wang 1,2,6, CEL Ng 1, Y Ito 1,2, M Araki 1, V Tergaonkar 2, G Huang 3, and M Osato 1,2,4,5
1 Cancer Science Institute of Singapore, National University of Singapore
2 Institute of Molecular and Cell Biology, Singapore
3 Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH, USA
4 Institute of Bioengineering and Nanotechnology, Singapore
5 Tohoku Medical Megabank Organisation, Tohoku University, Sendai, Japan