Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.
Publication/Presentation Date
12-1-2013
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.
Volume
9
Issue
12
First Page
840
Last Page
848
ISSN
1552-4469
Published In/Presented At
Hartwell, K. A., Miller, P. G., Mukherjee, S., Kahn, A. R., Stewart, A. L., Logan, D. J., Negri, J. M., Duvet, M., Järås, M., Puram, R., Dancik, V., Al-Shahrour, F., Kindler, T., Tothova, Z., Chattopadhyay, S., Hasaka, T., Narayan, R., Dai, M., Huang, C., Shterental, S., … Golub, T. R. (2013). Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nature chemical biology, 9(12), 840–848. https://doi.org/10.1038/nchembio.1367
Disciplines
Medicine and Health Sciences
PubMedID
24161946
Department(s)
Fellows and Residents
Document Type
Article