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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 LU and Puram, Rishi V. , et al. (2013) In Nature Chemical Biology 9(12). p.840-848
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Chemical Biology
volume
9
issue
12
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:24161946
  • scopus:84888014941
ISSN
1552-4450
DOI
10.1038/nchembio.1367
language
English
LU publication?
no
id
c62d46b6-2719-48fd-8af8-eeebe002f2b2
date added to LUP
2017-09-05 11:50:03
date last changed
2024-04-14 17:23:09
@article{c62d46b6-2719-48fd-8af8-eeebe002f2b2,
  abstract     = {{<p>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.</p>}},
  author       = {{Hartwell, Kimberly A. and Miller, Peter G. and Mukherjee, Siddhartha and Kahn, Alissa R. and Stewart, Alison L. and Logan, David J. and Negri, Joseph M. and Duvet, Mildred and Järås, Marcus and Puram, Rishi V. and Dancik, Vlado and Al-Shahrour, Fatima and Kindler, Thomas and Tothova, Zuzana and Chattopadhyay, Shrikanta and Hasaka, Thomas and Narayan, Rajiv and Dai, Mingji and Huang, Christina and Shterental, Sebastian and Chu, Lisa P. and Haydu, J. Erika and Shieh, Jae Hung and Steensma, David P. and Munoz, Benito and Bittker, Joshua A. and Shamji, Alykhan F. and Clemons, Paul A. and Tolliday, Nicola J. and Carpenter, Anne E. and Gilliland, D. Gary and Stern, Andrew M. and Moore, Malcolm A S and Scadden, David T and Schreiber, Stuart L. and Ebert, Benjamin L. and Golub, Todd R}},
  issn         = {{1552-4450}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{840--848}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Chemical Biology}},
  title        = {{Niche-based screening identifies small-molecule inhibitors of leukemia stem cells}},
  url          = {{http://dx.doi.org/10.1038/nchembio.1367}},
  doi          = {{10.1038/nchembio.1367}},
  volume       = {{9}},
  year         = {{2013}},
}