Thursday, December 5, 2013
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Assays & screens
system to screen for selective inhibitors of leukemia stem cells (LSCs)
A leukemia-stroma coculture
system could be used in high throughput screens for compounds that
selectively inhibit LSCs. The 384-well system cocultures primary,
LSC-enriched cell populations with bone marrow stromal cells and uses an
automated machine-learning algorithm to identify compounds that could inhibit
a behavior called cobblestone area formation. The system plus a series of
safety filters were used to screen a library of 14,718 compounds, which
yielded 15 top hits that selectively inhibited LSCs over normal hematopoietic
stem and progenitor cells (HSPCs) and lacked toxicity against two bone marrow
stromal cell types. Follow-up validation studies on one of the top screening
hits, the generic HMG-CoA reductase inhibitor
showed that the drug selectively killed LSCs over normal HSPCs in culture and
prevented the development of leukemia in a mouse model. Next steps could
include evaluating lovastatin and other top screening hits in combination
with existing leukemia drugs in animal models.
Published online Dec. 5, 2013
Patent and licensing status
Hartwell, K.A. et al.
Nat. Chem. Biol.; published online Oct. 27, 2013;
Contact: Todd R. Golub, Broad Institute of MIT and Harvard, Cambridge,
Contact: Benjamin L. Ebert, same affiliation as above
Contact: Stuart L. Schreiber, same affiliation as above
Contact: David T. Scadden, same affiliation as above
Contact: Malcolm A.S. Moore, Memorial Sloan-Kettering Cancer
New York, N.Y.
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