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Niche-based screening identifies small-molecule inhibitors of leukemia stem cells.
|Publication Type||Journal Article|
|Authors||Hartwell, KA, Miller PG, Mukherjee S., Kahn AR, Stewart AL, Logan DJ, Negri JM, 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., Chu LP, Haydu JE, Shieh JH, Steensma DP, Munoz B., Bittker JA, Shamji AF, Clemons PA, Tolliday NJ, Carpenter AE, Gilliland DG, Stern AM, Moore MA, Scadden DT, Schreiber SL, Ebert BL, and Golub T. R.|
|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.|
|Year of Publication||2013|
|Journal||Nature chemical biology|
|Date Published (YYYY/MM/DD)||2013/12/01|