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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.

SUBMITTER: Hartwell KA 

PROVIDER: S-EPMC4009363 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Hartwell Kimberly A KA   Miller Peter G PG   Mukherjee Siddhartha S   Kahn Alissa R AR   Stewart Alison L AL   Logan David J DJ   Negri Joseph M JM   Duvet Mildred M   Järås Marcus M   Puram Rishi R   Dancik Vlado V   Al-Shahrour Fatima F   Kindler Thomas T   Tothova Zuzana Z   Chattopadhyay Shrikanta S   Hasaka Thomas T   Narayan Rajiv R   Dai Mingji M   Huang Christina C   Shterental Sebastian S   Chu Lisa P LP   Haydu J Erika JE   Shieh Jae Hung JH   Steensma David P DP   Munoz Benito B   Bittker Joshua A JA   Shamji Alykhan F AF   Clemons Paul A PA   Tolliday Nicola J NJ   Carpenter Anne E AE   Gilliland D Gary DG   Stern Andrew M AM   Moore Malcolm A S MAS   Scadden David T DT   Schreiber Stuart L SL   Ebert Benjamin L BL   Golub Todd R TR  

Nature chemical biology 20131027 12


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-stro  ...[more]

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