Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

Research output: Contribution to journalArticle

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.

Details

Authors
  • Kimberly A. Hartwell
  • Peter G. Miller
  • Siddhartha Mukherjee
  • Alissa R. Kahn
  • Alison L. Stewart
  • David J. Logan
  • Joseph M. Negri
  • Mildred Duvet
  • Rishi V. Puram
  • Vlado Dancik
  • Fatima Al-Shahrour
  • Thomas Kindler
  • Zuzana Tothova
  • Shrikanta Chattopadhyay
  • Thomas Hasaka
  • Rajiv Narayan
  • Mingji Dai
  • Christina Huang
  • Sebastian Shterental
  • Lisa P. Chu
  • J. Erika Haydu
  • Jae Hung Shieh
  • David P. Steensma
  • Benito Munoz
  • Joshua A. Bittker
  • Alykhan F. Shamji
  • Paul A. Clemons
  • Nicola J. Tolliday
  • Anne E. Carpenter
  • D. Gary Gilliland
  • Andrew M. Stern
  • Malcolm A S Moore
  • David T Scadden
  • Stuart L. Schreiber
  • Benjamin L. Ebert
  • Todd R Golub
External organisations
  • Broad Institute
  • Brigham and Women's Hospital / Harvard Medical School
  • Harvard Medical School
  • Massachusetts General Hospital
  • Columbia University
  • Memorial Sloan-Kettering Cancer Center
  • Harvard University
  • Howard Hughes Medical Institute
  • University of Pittsburgh
  • Dana-Farber Cancer Institute
  • Cochin Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)840-848
Number of pages9
JournalNature Chemical Biology
Volume9
Issue number12
StatePublished - 2013 Dec
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes