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

Meaghan Boileau, Margret Shirinian, Tenzin Gayden, Ashot S. Harutyunyan, Carol C. L. Chen, Leonie G. Mikael, Heather M. Duncan, Andrea L. Neumann, Patricia Arreba-Tutusaus, Nicolas Jay, Michele Zeinieh, Katya Rossokhata, Yelu Zhang, Hamid Nikbakht, Carine Mouawad, Radwan Massoud, Felice Frey, Rihab Nasr, Jean El Cheikh, Marwan El Sabban, Claudia L. Kleinman, Rami Mahfouz, Mark D. Minden, Nada Jabado, Ali Bazarbachi and Kolja Eppert ()
Additional contact information
Meaghan Boileau: McGill University and McGill University Heath Centre Research Institute
Margret Shirinian: American University of Beirut
Tenzin Gayden: McGill University
Ashot S. Harutyunyan: McGill University
Carol C. L. Chen: McGill University
Leonie G. Mikael: McGill University and McGill University Heath Centre Research Institute
Heather M. Duncan: McGill University and McGill University Heath Centre Research Institute
Andrea L. Neumann: Research Institute of the McGill University Health Centre and McGill University
Patricia Arreba-Tutusaus: Research Institute of the McGill University Health Centre and McGill University
Nicolas Jay: McGill University
Michele Zeinieh: McGill University
Katya Rossokhata: McGill University
Yelu Zhang: Research Institute of the McGill University Health Centre and McGill University
Hamid Nikbakht: McGill University
Carine Mouawad: American University of Beirut
Radwan Massoud: American University of Beirut
Felice Frey: American University of Beirut
Rihab Nasr: American University of Beirut
Jean El Cheikh: American University of Beirut
Marwan El Sabban: American University of Beirut
Claudia L. Kleinman: McGill University
Rami Mahfouz: American University of Beirut
Mark D. Minden: University of Toronto
Nada Jabado: McGill University
Ali Bazarbachi: American University of Beirut
Kolja Eppert: McGill University and McGill University Heath Centre Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10705-z

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