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PARI (PARPBP) suppresses replication stress-induced myeloid differentiation in leukemia cells

Oncogene volume 38, pages 5530–5540 (2019)Cite this article

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Abstract

Hyperproliferative cancer cells face increased replication stress, which can result in accumulation of DNA damage. As DNA damage can arrest proliferation, and, in the case of myeloid leukemia, induce differentiation of cancer cells, understanding the mechanisms that regulate the replication stress response is paramount. Here, we show that PARI, a replisome protein involved in regulating DNA repair and replication stress, suppresses differentiation of myeloid leukemia cells. We show that PARI is overexpressed in myeloid leukemia cells, and its knockdown reduces leukemia cell proliferation in vitro and in vivo in xenograft mouse models. PARI depletion enhances replication stress and DNA-damage accumulation, coupled with increased myeloid differentiation. Mechanistically, we show that PARI inhibits activation of the NF-κB pathway, which can initiate p21-mediated differentiation and proliferation arrest. Finally, we show that PARI expression negatively correlates with expression of differentiation markers in clinical myeloid leukemia samples, suggesting that targeting PARI may restore differentiation ability of leukemia cells and antagonize their proliferation.

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Acknowledgments

We would like to thank Dr. Alan D’Andrea for EUFA130 cells, Dr. Chandrika Gowda for experimental advice, Daniel Constantin for technical support, and the Penn State College of Medicine Flow Cytometry and Genome Sciences cores. This work was supported by: the Department of Defense (award CA140303) and the St. Baldrick Foundation (to GLM); NIH R01CA209829, R01CA213912, Alex’s Lemonade Stand, Hyundai Hope on Wheels Scholar Grant, and Bear Necessities Pediatric Cancer Foundation (to SD).

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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, Emily M. Schleicher & George-Lucian Moldovan

  2. Department of Pediatrics, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Chunhua Song & Sinisa Dovat

  3. Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

    Raghavendra Gowda & Gavin Robertson

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Correspondence to George-Lucian Moldovan.

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Nicolae, C.M., O’Connor, M.J., Schleicher, E.M. et al. PARI (PARPBP) suppresses replication stress-induced myeloid differentiation in leukemia cells. Oncogene 38, 5530–5540 (2019). https://doi.org/10.1038/s41388-019-0810-x

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