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

Claudia M. Nicolae, Michael J. O’Connor, Emily M. Schleicher, Chunhua Song, Raghavendra Gowda, Gavin Robertson, Sinisa Dovat, George Lucian Moldovan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5530-5540
Number of pages11
JournalOncogene
Volume38
Issue number27
DOIs
StatePublished - Jul 4 2019

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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