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.
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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.).
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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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Yeh, JR., Munson, K., Elagib, K. et al. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nat Chem Biol 5, 236–243 (2009). https://doi.org/10.1038/nchembio.147
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DOI: https://doi.org/10.1038/nchembio.147
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