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

Author

Listed:
  • Meaghan Boileau

    (McGill University and McGill University Heath Centre Research Institute)

  • Margret Shirinian

    (American University of Beirut
    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
    Jewish General Hospital)

  • 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
    McGill University and Génome Québec Innovation Centre)

  • 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
    Jewish General Hospital)

  • Rami Mahfouz

    (American University of Beirut)

  • Mark D. Minden

    (University of Toronto
    University of Toronto)

  • Nada Jabado

    (McGill University
    McGill University and McGill University Heath Centre Research Institute)

  • Ali Bazarbachi

    (American University of Beirut
    American University of Beirut)

  • Kolja Eppert

    (McGill University and McGill University Heath Centre Research Institute)

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.

Suggested Citation

  • 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 & Mich, 2019. "Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10705-z
    DOI: 10.1038/s41467-019-10705-z
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