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Nat Chem Biol DOI:10.1038/nchembio.1367

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

Publication TypeJournal Article
Year of Publication2013
AuthorsHartwell, KA, Miller, PG, Mukherjee, S, Kahn, AR, Stewart, AL, Logan, DJ, Negri, JM, Duvet, M, Järås, M, Puram, R, Dančík, V, Al-Shahrour, F, Kindler, T, Tothova, Z, Chattopadhyay, S, Hasaka, T, Narayan, R, Dai, M, Huang, C, Shterental, S, Chu, LP, J Haydu, E, Shieh, JHung, Steensma, DP, Munoz, B, Bittker, JA, Shamji, AF, Clemons, PA, Tolliday, NJ, Carpenter, AE, D Gilliland, G, Stern, AM, Moore, MAS, Scadden, DT, Schreiber, SL, Ebert, BL, Golub, TR
JournalNat Chem Biol
Volume9
Issue12
Pages840-8
Date Published2013 Dec
ISSN1552-4469
KeywordsAntineoplastic Agents, Cell Line, Tumor, Drug Screening Assays, Antitumor, Hematopoietic Stem Cells, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Leukemia, Lovastatin, Neoplastic 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.

URLhttp://dx.doi.org/10.1038/nchembio.1367
DOI10.1038/nchembio.1367
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24161946?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID24161946
PubMed Central IDPMC4009363
Grant ListUL1RR024924 / RR / NCRR NIH HHS / United States
K08 CA158149 / CA / NCI NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
U54CA112962 / CA / NCI NIH HHS / United States
R01 GM089652 / GM / NIGMS NIH HHS / United States
UL1 RR024924 / RR / NCRR NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U01HL1004402 / HL / NHLBI NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
T32 HL007623 / HL / NHLBI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States