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Nat Commun. 2020 Mar 16;11(1):1406. doi: 10.1038/s41467-020-15221-z.

Chromatin accessibility promotes hematopoietic and leukemia stem cell activity.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
3
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
6
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA.
7
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. andrew_lane@dfci.harvard.edu.
9
Broad Institute of Harvard and MIT, Cambridge, MA, USA. andrew_lane@dfci.harvard.edu.

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.

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