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NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation

Oncogene volume 37, pages 3647–3656 (2018)Cite this article

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Abstract

DNA damage exposure is a major modifier of cell fate in both normal and cancer tissues. In response to DNA damage, myeloid leukemia cells activate a poorly understood terminal differentiation process. Here, we show that the NFκB pathway directly activates expression of the proliferation inhibitor p21 in response to DNA damage in myeloid leukemia cells. In order to understand the role of this unexpected regulatory event, we ablated the NFκB binding site we identified in the p21 promoter, using CRISPR/Cas9-mediated genome editing. We found that NFκB-mediated p21 activation controls DNA damage-induced myeloid differentiation. Our results uncover a p53-independent pathway for p21 activation involved in controlling hematopoietic cell fate.

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Acknowledgements

We would like to thank Wafik el-Deiry, Sinisa Dovat, David Claxton, Gregory Yochum, Sergei Grigoryev, James Broach, and the Penn State Flow Cytometry Core for materials, advice, and support. This work was supported by the Department of Defense (award CA140303) and the St. Baldrick Foundation.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Claudia M. Nicolae, Michael J. O’Connor, Daniel Constantin & George-Lucian Moldovan

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  1. Claudia M. Nicolae
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  2. Michael J. O’Connor
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  4. George-Lucian Moldovan
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Correspondence to George-Lucian Moldovan.

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Nicolae, C.M., O’Connor, M.J., Constantin, D. et al. NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation. Oncogene 37, 3647–3656 (2018). https://doi.org/10.1038/s41388-018-0219-y

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