{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:58:32Z","timestamp":1787752712650,"version":"build-2784847793"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL128173"],"award-info":[{"award-number":["R01HL128173"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alex\u2019s Lemonade Stand Foundation Innovation Award","award":["2012\/04\/A\/ST7\/00353"],"award-info":[{"award-number":["2012\/04\/A\/ST7\/00353"]}]},{"name":"Alex\u2019s Lemonade Stand Foundation Innovation Award","award":["2016\/23\/D\/ST7\/03665"],"award-info":[{"award-number":["2016\/23\/D\/ST7\/03665"]}]},{"name":"National Science Center","award":["T32 CA096520-14A1"],"award-info":[{"award-number":["T32 CA096520-14A1"]}]},{"name":"National Science Center","award":["R01 HL136333"],"award-info":[{"award-number":["R01 HL136333"]}]},{"name":"National Science Center","award":["R01 HL134880"],"award-info":[{"award-number":["R01 HL134880"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Severe congenital neutropenia (SCN) is a rare blood disorder characterised by abnormally low levels of circulating neutrophils. The most common recurrent mutations that cause SCN involve neutrophil elastase (ELANE). The treatment of choice for SCN is the administration of granulocyte-colony stimulating factor (G-CSF), which increases the neutrophil number and improves the survival and quality of life. Long-term survival is however linked to the development of myelodysplastic syndrome\/acute myeloid leukemia (MDS\/AML). About 70% of MDS\/AML patients acquire nonsense mutations affecting the cytoplasmic domain of CSF3R (the G-CSF receptor). About 70% of SCN patients with AML harbour additional mutations in RUNX1. We hypothesised that this coding region of CSF3R constitutes a hotspot vulnerable to mutations resulting from excessive oxidative stress or endoplasmic reticulum (ER) stress. We used the murine Ba\/F3 cell line to measure the effect of induced oxidative or ER stress on the mutation rate in our hypothesised hotspot of the exogenous human CSF3R, the corresponding region in the endogenous Csf3r, and Runx1. Ba\/F3 cells transduced with the cDNA for partial C-terminal of CSF3R fused in-frame with a green fluorescent protein (GFP) tag were subjected to stress-inducing treatment for 30 days (~51 doubling times). The amplicon-based targeted deep sequencing data for days 15 and 30 samples show that although there was increased mutagenesis observed in all the three genes of interest (partial CSF3R, Csf3r and Runx1), there were more mutations in the GFP region compared with the partial CSF3R region. Our findings also indicate that there is no correlation between the stress-inducing chemical treatments and mutagenesis in Ba\/F3 cells. Our data suggest that oxidative or ER stress induction does not promote genomic instability, affecting partial C-terminal of the transduced CSF3R, the endogenous Csf3R and the endogenous Runx1 in Ba\/F3 cells that could account for these targets to being mutational hotspots. We conclude that other mechanisms to acquire mutations of CSF3R that help drive the evolution of SCN to MDS\/AML.<\/jats:p>","DOI":"10.1093\/mutage\/geaa027","type":"journal-article","created":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T11:20:58Z","timestamp":1600773658000},"page":"381-389","source":"Crossref","is-referenced-by-count":6,"title":["Effect of the unfolded protein response and oxidative stress on mutagenesis in <i>CSF3R<\/i>: a model for evolution of severe congenital neutropenia to myelodysplastic syndrome\/acute myeloid leukemia"],"prefix":"10.1093","volume":"35","author":[{"given":"Adya","family":"Sapra","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Cancer Biology, and Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Jaksik","sequence":"additional","affiliation":[{"name":"Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hrishikesh","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cancer Biology, and Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Biesiadny","sequence":"additional","affiliation":[{"name":"Department of Statistics, Rice University, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Kimmel","sequence":"additional","affiliation":[{"name":"Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland"},{"name":"Department of Statistics, Rice University, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3575-6401","authenticated-orcid":false,"given":"Seth J","family":"Corey","sequence":"additional","affiliation":[{"name":"Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,29]]},"reference":[{"key":"2021012909462802600_CIT0001","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev-immunol-030409-101259","article-title":"Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes","volume":"29","author":"Klein","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"2021012909462802600_CIT0002","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1182\/asheducation-2009.1.344","article-title":"Congenital neutropenia","author":"Klein","year":"2009","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"2021012909462802600_CIT0003","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1365-2141.2009.07888.x","article-title":"Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia","volume":"147","author":"Xia","year":"2009","journal-title":"Br. J. Haematol."},{"key":"2021012909462802600_CIT0004","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1182\/blood-2005-11-4689","article-title":"Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response","volume":"108","author":"K\u00f6llner","year":"2006","journal-title":"Blood"},{"key":"2021012909462802600_CIT0005","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1182\/blood-2010-10-311704","article-title":"Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane","volume":"117","author":"Nanua","year":"2011","journal-title":"Blood"},{"key":"2021012909462802600_CIT0006","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1182\/blood-2013-07-513242","article-title":"Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms","volume":"123","author":"Tidwell","year":"2014","journal-title":"Blood"},{"key":"2021012909462802600_CIT0007","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1189\/jlb.5A1016-445R","article-title":"Elastase inhibitors as potential therapies for ELANE-associated neutropenia","volume":"102","author":"Makaryan","year":"2017","journal-title":"J. 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Neurosci."}],"container-title":["Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mutage\/article-pdf\/35\/5\/381\/36141539\/geaa027.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mutage\/article-pdf\/35\/5\/381\/36141539\/geaa027.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T09:47:45Z","timestamp":1611913665000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mutage\/article\/35\/5\/381\/6123387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,1]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,1,29]]},"published-print":{"date-parts":[[2020,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/mutage\/geaa027","relation":{},"ISSN":["0267-8357","1464-3804"],"issn-type":[{"value":"0267-8357","type":"print"},{"value":"1464-3804","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,9,1]]},"published":{"date-parts":[[2020,9,1]]}}}