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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-12

AUTHORS

Kimberly A Hartwell, Peter G Miller, Siddhartha Mukherjee, Alissa R Kahn, Alison L Stewart, David J Logan, Joseph M Negri, Mildred Duvet, Marcus Järås, Rishi 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

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. More... »

PAGES

840-848

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nchembio.1367

DOI

http://dx.doi.org/10.1038/nchembio.1367

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1045763666

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24161946


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