Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L.
Chromosomal translocation is a common cause of leukaemia and the most common chromosome translocations found in leukaemia patients involve the mixed lineage leukaemia (MLL) gene. AF10 is one of more than 30 MLL fusion partners in leukaemia. We have recently demonstrated that the H3K79 methyltransferase hDOT1L contributes to MLL-AF10-mediated leukaemogenesis through its interaction with AF10 (ref. 5). In addition to MLL, AF10 has also been reported to fuse to CALM (clathrin-assembly protein-like lymphoid-myeloid) in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML). Here, we analysed the molecular mechanism of leukaemogenesis by CALM-AF10. We demonstrate that CALM-AF10 fusion is both necessary and sufficient for leukaemic transformation. Additionally, we provide evidence that hDOT1L has an important role in the transformation process. hDOT1L contributes to CALM-AF10-mediated leukaemic transformation by preventing nuclear export of CALM-AF10 and by upregulating the Hoxa5 gene through H3K79 methylation. Thus, our study establishes CALM-AF10 fusion as a cause of leukaemia and reveals that mistargeting of hDOT1L and upregulation of Hoxa5 through H3K79 methylation is the underlying mechanism behind leukaemia caused by CALM-AF10 fusion.
Okada
Yuki
Y
Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Jiang
Qi
Q
Lemieux
Margot
M
Jeannotte
Lucie
L
Su
Lishan
L
Zhang
Yi
Y
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism / Q000473:pathology*; D008780:Methyltransferases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034041:Monomeric Clathrin Assembly Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000502:physiology*; D020298:U937 Cells; D015854:Up-Regulation
C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; C092513:MLLT10 protein, human; C490477:Mllt10 protein, mouse; D034041:Monomeric Clathrin Assembly Proteins; D015514:Oncogene Proteins, Fusion; C439003:PICALM protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase