E-GEOD-51033 - Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

Status
Released on 20 September 2013, last updated on 3 June 2014
Organism
Mus musculus
Samples (7)
Array (1)
Protocols (6)
Description
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 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 suggest that statins should be re-evaluated as anti-leukemia agents, and illustrate the power of merging physiologically-relevant models with high-throughput screening. Freshly isolated LSCe cells were treated with either 5µM BRD7116 or DMSO vehicle control for 6 hours in suspension in IMDM (12440053, Invitrogen), 10% FBS. Total RNA was extracted from the cells, labeled, and hybridized to MouseRef-8 v2.0 Expression BeadChips. Hartwell, K.A. et al., In Press (full citation forthcoming)
Experiment type
transcription profiling by array 
Contacts
Kimberly Hartwell <hartwell@broadinstitute.org>, Alison L Stewart, Alissa R Kahn, Alykhan F Shamji, Andrew M Stern, Anne E Carpenter, Benito Munoz, Benjamin L Ebert, Christina Huang, D G Gilliland, David J Logan, David P Steensma, David T Scadden, Fatima AlShahrour, J E Haydu, Jae H Shieh, Joseph M Negri, Joshua A Bittker, Kimberly A Hartwell, Lisa P Chu, Malcolm A Moore, Marcus Järås, Mildred Duvet, Mingji Dai, Nicola J Tolliday, Paul A Clemons, Peter G Miller, Rajiv Narayan, Rishi Puram, Sebastian Shterental, Shrikanta Chattopadhyay, Siddhartha Mukherjee, Stuart L Schreiber, Thomas Hasaka, Thomas Kindler, Todd R Golub, Vlado Dancik, Zuzana Tothova
MIAME
PlatformsProtocolsFactorsProcessedRaw
Files
Investigation descriptionE-GEOD-51033.idf.txt
Sample and data relationshipE-GEOD-51033.sdrf.txt
Processed data (1)E-GEOD-51033.processed.1.zip
Array designA-MEXP-1174.adf.txt
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