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Cell. 2016 Apr 7;165(2):303-16. doi: 10.1016/j.cell.2016.03.015.

Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML.

Author information

1
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
2
Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
3
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
5
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
6
Translational Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
7
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Hematology and Oncology, Hanover Medical School, Hanover 30625, Germany.
8
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Clinical Genetics, Lund University, Lund 22184, Sweden.
9
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
10
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
11
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Translational Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
12
Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
13
Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: bebert@partners.org.

Abstract

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.

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PMID:
27058663
PMCID:
PMC4826477
DOI:
10.1016/j.cell.2016.03.015
[Indexed for MEDLINE]
Free PMC Article

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