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Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

Author

Listed:
  • Lucia Cabal-Hierro

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Peter Galen

    (Broad Institute of Harvard and MIT
    Department of Pathology, Massachusetts General Hospital, Harvard Medical School)

  • Miguel A. Prado

    (Department of Cell Biology, Harvard Medical School)

  • Kelly J. Higby

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Katsuhiro Togami

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Cody T. Mowery

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Joao A. Paulo

    (Department of Cell Biology, Harvard Medical School)

  • Yingtian Xie

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute)

  • Paloma Cejas

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute)

  • Takashi Furusawa

    (Laboratory of Metabolism, National Cancer Institute)

  • Michael Bustin

    (Laboratory of Metabolism, National Cancer Institute)

  • Henry W. Long

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute)

  • David B. Sykes

    (Center for Regenerative Medicine, Massachusetts General Hospital)

  • Steven P. Gygi

    (Department of Cell Biology, Harvard Medical School)

  • Daniel Finley

    (Department of Cell Biology, Harvard Medical School)

  • Bradley E. Bernstein

    (Broad Institute of Harvard and MIT
    Department of Pathology, Massachusetts General Hospital, Harvard Medical School)

  • Andrew A. Lane

    (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
    Broad Institute of Harvard and MIT)

Abstract

Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.

Suggested Citation

  • Lucia Cabal-Hierro & Peter Galen & Miguel A. Prado & Kelly J. Higby & Katsuhiro Togami & Cody T. Mowery & Joao A. Paulo & Yingtian Xie & Paloma Cejas & Takashi Furusawa & Michael Bustin & Henry W. Lon, 2020. "Chromatin accessibility promotes hematopoietic and leukemia stem cell activity," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15221-z
    DOI: 10.1038/s41467-020-15221-z
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