Chromatin accessibility promotes hematopoietic and leukemia stem cell activity

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. Long, David B. Sykes, Steven P. Gygi, Daniel Finley, Bradley E. Bernstein and Andrew A. Lane ()
Additional contact information
Lucia Cabal-Hierro: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Peter Galen: Broad Institute of Harvard and MIT
Miguel A. Prado: Department of Cell Biology, Harvard Medical School
Kelly J. Higby: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Katsuhiro Togami: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Cody T. Mowery: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Joao A. Paulo: Department of Cell Biology, Harvard Medical School
Yingtian Xie: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
Paloma Cejas: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
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
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
Andrew A. Lane: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15221-z

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