{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:27:50Z","timestamp":1787167670879,"version":"build-2736575974"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine\/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR\/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1\/2 serine\/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1\/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-\/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.<\/jats:p>","DOI":"10.1182\/blood.2022018428","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T16:36:17Z","timestamp":1672331777000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":3,"title":["DNA polymerase theta protects leukemia cells from metabolic-induced DNA damage"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6662-9122","authenticated-orcid":false,"given":"Umeshkumar","family":"Vekariya","sequence":"first","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8414-253X","authenticated-orcid":false,"given":"Monika Maria","family":"Toma","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Nieborowska-Skorska","sequence":"additional","affiliation":[{"name":"Temple University, School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bac Viet","family":"Le","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Caron","sequence":"additional","affiliation":[{"name":"Laval University Cancer Research Center, Qu\u00e9bec City, Qu\u00e9bec, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Mariya","family":"Kukuyan","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Sullivan-Reed","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4965-828X","authenticated-orcid":false,"given":"Paulina","family":"Podszywalow-Bartnicka","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumaraswamy Naidu","family":"Chitrala","sequence":"additional","affiliation":[{"name":"University of Houston, Sugar Land, Texas, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9563-3358","authenticated-orcid":false,"given":"Jessica","family":"Atkins","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-7993","authenticated-orcid":false,"given":"Malgorzata","family":"Drzewiecka","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjuan","family":"Feng","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5627-6693","authenticated-orcid":false,"given":"Joe","family":"Chan","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8509-8494","authenticated-orcid":false,"given":"Srinivas","family":"Chatla","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Golovine","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-0220","authenticated-orcid":false,"given":"Jaroslav","family":"Jelinek","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, Camden, New Jersey, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Sliwinski","sequence":"additional","affiliation":[{"name":"University of Lodz, Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4929-5829","authenticated-orcid":false,"given":"Jayashri","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-5793","authenticated-orcid":false,"given":"Ksenia","family":"Matlawska-Wasowska","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham, Birmingham, Alabama, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurushankar","family":"Chandramouly","sequence":"additional","affiliation":[{"name":"Thomas Jefferson University, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Nejati","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz A","family":"Wasik","sequence":"additional","affiliation":[{"name":"Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7330-0106","authenticated-orcid":false,"given":"Stephen","family":"Sykes","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis School of Medicine, Saint Louis, Missouri, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Piwocka","sequence":"additional","affiliation":[{"name":"Nencki Institute of Experimental Biology, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7409-4204","authenticated-orcid":false,"given":"Emir","family":"Hadzijusufovic","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-5095","authenticated-orcid":false,"given":"Peter","family":"Valent","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T","family":"Pomerantz","sequence":"additional","affiliation":[{"name":"Thomas Jefferson University, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Morton","sequence":"additional","affiliation":[{"name":"Temple University School of Pharmacy, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0527-3684","authenticated-orcid":false,"given":"Wayne","family":"Childers","sequence":"additional","affiliation":[{"name":"Temple University School of Pharmacy, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Paietta","sequence":"additional","affiliation":[{"name":"Montefiore Medical Center, Bronx, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross L.","family":"Levine","sequence":"additional","affiliation":[{"name":"Memorial Sloan-Kettering Cancer Center, New York, New York, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Tallman","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7322-0392","authenticated-orcid":false,"given":"Hugo","family":"Fernandez","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center, Pembroke Pines, Florida, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-6302","authenticated-orcid":false,"given":"Mark R","family":"Litzow","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Rochester, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9177-552X","authenticated-orcid":false,"given":"Gaorav","family":"Gupta","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Masson","sequence":"additional","affiliation":[{"name":"Laval University Cancer Research Center, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[{"name":"Temple University School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2022,12,29]]},"updated-by":[{"DOI":"10.1182\/blood.2026035139","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000}}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2022018428\/2027086\/blood.2022018428.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2022018428\/2027086\/blood.2022018428.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T16:36:17Z","timestamp":1672331777000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2022018428\/493945\/DNA-polymerase-theta-protects-leukemia-cells-from"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,29]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2022018428","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,29]]},"article-number":"blood.2022018428"}}