title: Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML.
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.
authors.affiliation: 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.
authors.forename: Rishi V
authors.initials: RV
authors.lastname: Puram
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
authors.forename: Monika S
authors.initials: MS
authors.lastname: Kowalczyk
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
authors.forename: Carl G
authors.initials: CG
authors.lastname: de Boer
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: McConkey
authors.affiliation: 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.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.affiliation: Translational Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Tejero
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heckl
authors.affiliation: 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.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hubo
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Tamayo
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
authors.affiliation: 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.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: 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.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: 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.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics*; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; D034741:RNA, Small Interfering; D056926:CLOCK Proteins; C538943:CLOCK protein, human