Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

Rishi V Puram; Monika S Kowalczyk; Carl G de Boer; Rebekka K Schneider; Peter G Miller; Marie McConkey; Zuzana Tothova; Héctor Tejero; Dirk Heckl; Marcus Järås; Michelle C Chen; Hubo Li; Alfred Tamayo; Glenn S Cowley; Orit Rozenblatt-Rosen; Fatima Al-Shahrour; Aviv Regev; Benjamin L Ebert

doi:10.1016/j.cell.2016.03.015

Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

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

Authors

Rishi V Puram¹, Monika S Kowalczyk², Carl G de Boer², Rebekka K Schneider³, Peter G Miller⁴, Marie McConkey³, Zuzana Tothova⁵, Héctor Tejero⁶, Dirk Heckl⁷, Marcus Järås⁸, Michelle C Chen³, Hubo Li⁹, Alfred Tamayo¹⁰, Glenn S Cowley², Orit Rozenblatt-Rosen², Fatima Al-Shahrour¹¹, Aviv Regev¹², Benjamin L Ebert¹³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ARNTL Transcription Factors / genetics*
Animals
CLOCK Proteins / genetics*
Circadian Rhythm
Disease Models, Animal
Gene Knockout Techniques
Hematopoiesis
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology*
Mice
Mice, Inbred C57BL
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
RNA Interference
RNA, Small Interfering / metabolism

Substances

ARNTL Transcription Factors
BMAL1 protein, human
Bmal1 protein, mouse
RNA, Small Interfering
CLOCK Proteins
CLOCK protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding