title: Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.
abstract: Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hartwell
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Alissa R
authors.initials: AR
authors.lastname: Kahn
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Stewart
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Logan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Negri
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Mildred
authors.initials: M
authors.lastname: Duvet
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Puram
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dancik
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Shrikanta
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hasaka
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Narayan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Mingji
authors.initials: M
authors.lastname: Dai
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Huang
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Shterental
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Chu
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J Erika
authors.initials: JE
authors.lastname: Haydu
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Jae Hung
authors.initials: JH
authors.lastname: Shieh
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Tolliday
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Harvard Medical School, Chevy Chase, MD 20815, USA.
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Malcolm A S
authors.initials: MAS
authors.lastname: Moore
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Howard Hughes Medical Institute, Harvard Medical School, Chevy Chase, MD 20815, USA.|Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Harvard Medical School, Chevy Chase, MD 20815, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006412:Hematopoietic Stem Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007938:Leukemia; D008148:Lovastatin / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin