Hartwell KA, Miller PG, Mukherjee S, Kahn AR, Stewart AL, Logan DJ, Negri JM, Duvet M, Jaras M, Puram R, et al. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol. 2013;9:840–848.
NOTES
Hartwell, Kimberly AMiller, Peter GMukherjee, SiddharthaKahn, Alissa RStewart, Alison LLogan, David JNegri, Joseph MDuvet, MildredJaras, MarcusPuram, RishiDancik, VladoAl-Shahrour, FatimaKindler, ThomasTothova, ZuzanaChattopadhyay, ShrikantaHasaka, ThomasNarayan, RajivDai, MingjiHuang, ChristinaShterental, SebastianChu, Lisa PHaydu, J ErikaShieh, Jae HungSteensma, David PMunoz, BenitoBittker, Joshua AShamji, Alykhan FClemons, Paul ATolliday, Nicola JCarpenter, Anne EGilliland, D GaryStern, Andrew MMoore, Malcolm A SScadden, David TSchreiber, Stuart LEbert, Benjamin LGolub, Todd RengUL1RR024924/RR/NCRR NIH HHS/K08 CA158149/CA/NCI NIH HHS/RL1HG004671/HG/NHGRI NIH HHS/T32 GM007753/GM/NIGMS NIH HHS/RL1CA133834/CA/NCI NIH HHS/RL1GM084437/GM/NIGMS NIH HHS/T32 CA009172/CA/NCI NIH HHS/P30 CA008748/CA/NCI NIH HHS/U54CA112962/CA/NCI NIH HHS/R01 GM089652/GM/NIGMS NIH HHS/UL1 RR024924/RR/NCRR NIH HHS/Howard Hughes Medical Institute/U01HL1004402/HL/NHLBI NIH HHS/RL1 GM084437/GM/NIGMS NIH HHS/U54 CA112962/CA/NCI NIH HHS/T32 HL007623/HL/NHLBI NIH HHS/N01CO12400/CA/NCI NIH HHS/RL1 HG004671/HG/NHGRI NIH HHS/RL1 CA133834/CA/NCI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.Nat Chem Biol. 2013 Dec;9(12):840-848. doi: 10.1038/nchembio.1367. Epub 2013 Oct 27.
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.
Last updated on 02/17/2021