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Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.
Hartwell, Kimberly A; Miller, Peter G; Mukherjee, Siddhartha; Kahn, Alissa R; Stewart, Alison L; Logan, David J; Negri, Joseph M; Duvet, Mildred; Järås, Marcus; Puram, Rishi; Dancik, Vlado; Al-Shahrour, Fatima; Kindler, Thomas; Tothova, Zuzana; Chattopadhyay, Shrikanta; Hasaka, Thomas; Narayan, Rajiv; Dai, Mingji; Huang, Christina; Shterental, Sebastian; Chu, Lisa P; Haydu, J Erika; Shieh, Jae Hung; Steensma, David P; Munoz, Benito; Bittker, Joshua A; Shamji, Alykhan F; Clemons, Paul A; Tolliday, Nicola J; Carpenter, Anne E; Gilliland, D Gary; Stern, Andrew M; Moore, Malcolm A S; Scadden, David T; Schreiber, Stuart L; Ebert, Benjamin L; Golub, Todd R.
Afiliação
  • Hartwell KA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Miller PG; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Mukherjee S; Harvard Medical School, Boston, MA 02115, USA.
  • Kahn AR; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Stewart AL; Harvard Medical School, Boston, MA 02115, USA.
  • Logan DJ; Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Negri JM; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • Duvet M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Järås M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Puram R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Dancik V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Al-Shahrour F; Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Kindler T; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Tothova Z; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Chattopadhyay S; Harvard Medical School, Boston, MA 02115, USA.
  • Hasaka T; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Narayan R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Dai M; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Huang C; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Shterental S; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Chu LP; Harvard Medical School, Boston, MA 02115, USA.
  • Haydu JE; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Shieh JH; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • Steensma DP; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Munoz B; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Bittker JA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Shamji AF; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • Clemons PA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Tolliday NJ; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Carpenter AE; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Gilliland DG; Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Stern AM; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
  • Moore MAS; Harvard Medical School, Boston, MA 02115, USA.
  • Scadden DT; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Schreiber SL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Ebert BL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Golub TR; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nat Chem Biol ; 9(12): 840-848, 2013 Dec.
Article em En | MEDLINE | ID: mdl-24161946
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Ensaios de Seleção de Medicamentos Antitumorais / Leucemia / Antineoplásicos Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Humans Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Ensaios de Seleção de Medicamentos Antitumorais / Leucemia / Antineoplásicos Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Humans Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Estados Unidos