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

Nature Chemical Biology volume 9, pages 840–848 (2013)Cite this article

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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.

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Figure 1: A high-throughput system for probing LSCe cells within a stromal niche.
Figure 2: New small molecule BRD7116 selectively targets LSCe cells by cell-autonomous and cell-non-autonomous mechanisms.
Figure 3: Lovastatin selectively inhibits mouse and human leukemia cells in co-culture.
Figure 4: Sensitivity of LSCe cells to HMGCR inhibition.

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Acknowledgements

We wish to thank L. VerPlank, V. Raksakulthai, A. Liberzon, M. Palmer, G. Cowley, J. Burbank, P. Aspesi Jr., M. Bliss-Moreau, D. Barker, B. Wagner, A. Krivtsov, S.A. Armstrong, R. Karmacharya, J. Perez, R. Onofrio, D. Thomas, R. Busanelli, D. Auclair, K. Masson, J. Du, C. Moore, M. Kharas, Y. Hoshida, D. Bachovchin, A. Mullally, J. Grabarek, A. Fraser, A. Basu, J. Cheah, N. Bodycombe, C. Mulrooney, S. Johnston, G. Walzer, D. Wilpitz, A. Bracha, A. Fabian, C. Hon, J. McGrath, C. Hartland, M. Hickey, T.R. Jones, M. Bray, K. Sokolnicki, R. Okabe, M. Paktinat, M. McConkey, L. Gaffney, L. Solomon, K. Rose and Broad Compound Management. We also thank the Golub, Gilliland and Ebert laboratories for scientific discussions and technical expertise. This work was funded by grants from the Starr Cancer Consortium (SCC Award l1-A50), the US National Institutes of Health (U54CA112962, U01HL1004402, T32 HL007623, T32 GM007753, N01-CO-12400, R01 GM089652, RL1CA133834, 20XS139, RL1HG004671, RL1CA133834, RL1GM084437 and UL1RR024924) and the US National Science Foundation (DBI 1148823). The content of this publication is solely the responsibility of the authors and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. T.R.G., D.G.G. and S.L.S. are investigators at the Howard Hughes Medical Institute.

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Author notes

  1. Siddhartha Mukherjee, D Gary Gilliland & Andrew M Stern

    Present address: Present addresses: Department of Medicine and Irving Cancer Research Center, Columbia University School of Medicine, New York, New York, USA (S.M.); Penn Medicine, Philadelphia, Pennsylvania, USA (D.G.G.); Department of Computational and Systems Biology, University of Pittsburgh Drug Discovery Institute, Pittsburgh, Pennsylvania, USA (A.M.S.).,

  2. Kimberly A Hartwell and Peter G Miller: These authors contributed equally to this work.

Authors and Affiliations

  1. Broad Institute, Cambridge, Massachusetts, USA

    Kimberly A Hartwell, Alison L Stewart, David J Logan, Joseph M Negri, Mildred Duvet, Vlado Dancik, Fatima Al-Shahrour, Shrikanta Chattopadhyay, Thomas Hasaka, Rajiv Narayan, Mingji Dai, Christina Huang, Benito Munoz, Joshua A Bittker, Alykhan F Shamji, Paul A Clemons, Nicola J Tolliday, Anne E Carpenter, D Gary Gilliland, Andrew M Stern, David T Scadden, Stuart L Schreiber, Benjamin L Ebert & Todd R Golub

  2. Department of Medicine, Division of Hematology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Kimberly A Hartwell, Peter G Miller, Marcus Järås, Rishi Puram, Fatima Al-Shahrour, Thomas Kindler, Zuzana Tothova, Sebastian Shterental, Lisa P Chu, J Erika Haydu, D Gary Gilliland & Benjamin L Ebert

  3. Harvard Medical School, Boston, Massachusetts, USA

    Kimberly A Hartwell, Peter G Miller, Rishi Puram, Zuzana Tothova, David P Steensma, Benjamin L Ebert & Todd R Golub

  4. Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA

    Siddhartha Mukherjee, Mildred Duvet & David T Scadden

  5. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Alissa R Kahn & Jae Hung Shieh

  6. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA

    Shrikanta Chattopadhyay & David T Scadden

  7. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA

    Mingji Dai & Stuart L Schreiber

  8. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    David P Steensma, D Gary Gilliland & Benjamin L Ebert

  9. Howard Hughes Medical Institute, Harvard Medical School, Chevy Chase, Maryland, USA

    D Gary Gilliland, Stuart L Schreiber & Todd R Golub

  10. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Malcolm A S Moore

  11. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Todd R Golub

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Contributions

A.E.C., A.F.S., A.L.S., A.M.S., B.L.E., D.G.G., D.T.S., K.A.H., M.A.S.M., P.G.M., S.L.S., S.M. and T.R.G. designed the project strategy and interpreted results. A.E.C., A.L.S., A.M.S., D.G.G., D.J.L., D.T.S., J.A.B., J.E.H., J.M.N., K.A.H., N.J.T., P.G.M., S.L.S., S.M., S.S., T.H., T.K. and Z.T. developed the assay. A.L.S., D.J.L., J.A.B., J.M.N., K.A.H., M. Duvet, N.J.T., P.A.C., P.G.M., S.C., S.S. and T.H. conducted small-molecule screening. A.L.S., A.R.K., B.M., C.H., D.J.L., D.P.S., F.A.-S., J.A.B., J.H.S., J.M.N., K.A.H., L.P.C., M. Dai, M. Duvet, M.J., N.J.T., P.G.M., R.N., R.P., S.C., S.S., T.H. and V.D. conducted follow-up studies. A.M.S., B.L.E., K.A.H., P.G.M. and T.R.G. drafted the paper.

Corresponding authors

Correspondence to Malcolm A S Moore, David T Scadden, Stuart L Schreiber, Benjamin L Ebert or Todd R Golub.

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Hartwell, K., Miller, P., Mukherjee, S. et al. Niche-based screening identifies small-molecule inhibitors of leukemia stem cells. Nat Chem Biol 9, 840–848 (2013). https://doi.org/10.1038/nchembio.1367

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