DNA polymerase θ protects leukemia cells from metabolically induced DNA damage

Umeshkumar Vekariya, Monika Toma, Margaret Nieborowska-Skorska, Bac Viet Le, Marie Christine Caron, Anna Mariya Kukuyan, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Kumaraswamy N. Chitrala, Jessica Atkins, Malgorzata Drzewiecka, Wanjuan Feng, Joe Chan, Srinivas Chatla, Konstantin Golovine, Jaroslav Jelinek, Tomasz Sliwinski, Jayashri Ghosh, Ksenia Matlawska-Wasowska, Gurushankar ChandramoulyReza Nejati, Mariusz Wasik, Stephen M. Sykes, Katarzyna Piwocka, Emir Hadzijusufovic, Peter Valent, Richard T. Pomerantz, George Morton, Wayne Childers, Huaqing Zhao, Elisabeth M. Paietta, Ross L. Levine, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Gaorav P. Gupta, Jean Yves Masson, Tomasz Skorski

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK–dependent nonhomologous end-joining, was abrogated in Polq−/− murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.

Original languageEnglish
Pages (from-to)2372-2389
Number of pages18
JournalBlood
Volume141
Issue number19
DOIs
StatePublished - May 11 2023

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