Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness

Nature Communications

  ^{1    1    1    2    3    3    3    3    3    4    4    5    6    7    7    8    8    9    9    1,10    1,10    1,11    1,12    1,12    1,13    1,14} 

[1] 0000 0000 9064 4811, grid.63984.30, Research Institute of the McGill University Health Centre and McGill University, H4A 3J1, Montreal, QC, Canada;0000 0001 2157 2938, grid.17063.33, Princess Margaret Cancer Centre, University Health Network, University of Toronto, M5G 2C1, Toronto, ON, Canada;0000 0001 2157 2938, grid.17063.33, Department of Medicine, University of Toronto, M5S 1A8, Toronto, ON, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Human Genetics, McGill University, H3A 1B1, Montreal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Human Genetics, McGill University, H3A 1B1, Montreal, QC, Canada;0000 0000 9401 2774, grid.414980.0, Lady Davis Institute for Medical Research, Jewish General Hospital, H3T 1E2, Montréal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Human Genetics, McGill University, H3A 1B1, Montreal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, H4A 3J1, Montreal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Human Genetics, McGill University, H3A 1B1, Montreal, QC, Canada;grid.411640.6, McGill University and Génome Québec Innovation Centre, H3A 0G1, Montreal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Department of Pediatrics, McGill University and McGill University Heath Centre Research Institute, H4A 3J1, Montreal, QC, Canada;0000 0004 1936 8649, grid.14709.3b, Division of Experimental Medicine, McGill University and McGill University Heath Centre Research Institute, H4A 3J1, Montreal, QC, Canada;0000 0004 1936 9801, grid.22903.3a, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Internal Medicine, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Internal Medicine, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Internal Medicine, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, 1107 2020, Beirut, Lebanon;0000 0004 1936 9801, grid.22903.3a, Department of Pathology and Laboratory Medicine, American University of Beirut, 1107 2020, Beirut, Lebanon;

DOI  :  10.1038/s41467-019-10705-z

来源: publisher

【 摘 要 】

Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.

【 授权许可】

CC BY