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Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation

Nature Chemical Biology volume 5, pages 236243 (2009) | Download Citation

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Abstract

It has been proposed that inhibitors of an oncogene's effects on multipotent hematopoietic progenitor cell differentiation may change the properties of the leukemic stem cells and complement the clinical use of cytotoxic drugs. Using zebrafish, we developed a robust in vivo hematopoietic differentiation assay that reflects the activity of the oncogene AML1-ETO. Screening for modifiers of AML1-ETO–mediated hematopoietic dysregulation uncovered unexpected roles of COX-2– and β-catenin–dependent pathways in AML1-ETO function. This approach may open doors for developing therapeutics targeting oncogene function within leukemic stem cells.

  • Compound

    Nimesulide

  • Compound

    Rotenone

  • Compound

    Valproate

  • Compound

    Trichostatin A

  • Compound

    Cycloheximide

  • Compound

    Mundoserone

  • Compound

    Bithionol

  • Compound

    Dichlorophene

  • Compound

    Dicumarol

  • Compound

    NS-398

  • Compound

    Indomethacin

  • Compound

    Prostaglandin E2

  • Compound

    16,16-dimethyl prostaglandin E2

  • Compound

    6-Bromoindirubin-3'-oxime

  • Compound

    beta-Dihydrorotenone

  • Compound

    Deguelin

  • Compound

    alpha-Toxicarol

  • Compound

    Totarol-19-carboxylic acid

  • Compound

    2,4-Dinitrophenol

  • Compound

    3-Acetoxypregn-16-en-12,20-dione

  • Compound

    Pseudobaptigenin

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Acknowledgements

We thank E.R. Plovie and M.N. Rivera (Massachusetts General Hospital) and H. Clevers (Hubrecht Institute) for providing reagents, and C.L. Tsai, C. Sachidanandan and the members of the Developmental Biology Laboratory for helpful discussion. J.-R.J.Y. is supported by a Career Development Award (AG031300) from the National Institute of Aging. The authors received financial support from the National Cancer Institute (CA118498 to R.T.P.), the Mattina Proctor Foundation (to D.A.S) and the Claflin Distinguished Scholar Award (to J.-R.J.Y.).

Author information

Affiliations

  1. Developmental Biology Laboratory, Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts 02129, USA.

    • Jing-Ruey J Yeh
    • , Kathleen M Munson
    •  & Randall T Peterson
  2. Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.

    • Jing-Ruey J Yeh
    • , Kathleen M Munson
    • , David A Sweetser
    •  & Randall T Peterson
  3. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Jing-Ruey J Yeh
    • , Kathleen M Munson
    •  & Randall T Peterson
  4. Department of Pathology, PO Box 800904, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

    • Kamaleldin E Elagib
    •  & Adam N Goldfarb
  5. Department of Pediatrics, Division of Pediatric Hematology/Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • David A Sweetser

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Contributions

J.-R.J.Y designed and performed experiments, interpreted data and wrote the manuscript; K.M.M. designed and performed experiments and interpreted data; K.E.E. and A.N.G. provided critical reagents and advice; D.A.S. provided critical advice and edited the manuscript; R.T.P. designed experiments, interpreted data and edited the manuscript.

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DOI

https://doi.org/10.1038/nchembio.147

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