{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:25:00Z","timestamp":1787304300112,"version":"build-2736575974"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["ZIA SC 010378"],"award-info":[{"award-number":["ZIA SC 010378"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["ZIA BC 010983"],"award-info":[{"award-number":["ZIA BC 010983"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>T-cell acute lymphoblastic leukemia (T-ALL) patients generally respond well to chemotherapy, but T-ALL cells at relapse are typically resistant to chemotherapy. The specific mechanisms leading to chemoresistance are incompletely understood. We used Mcm2 hypomorph T-ALL cell lines, which are prone to copy number variant mutations, to identify acquired mutations that underlie chemoresistance. We found acquired copy number variants leading to resistance to a wide spectrum of chemotherapeutic agents and focused on cell lines that inactivated both Dck and Trp53, leading to cytarabine resistance and a unique mutational signature. This signature is characterized by C\u00a0&amp;gt;\u00a0T mutations in a GCG trinucleotide context, T\u00a0&amp;gt;\u00a0C in a GTC context, T\u00a0&amp;gt;\u00a0G in GTC and GTT contexts, and C\u00a0&amp;gt;\u00a0G in a GCC context. Ongoing cytarabine exposure is not required for this mutational signature. Further analyses revealed that the T\u00a0&amp;gt;\u00a0C in GTC context is associated with proliferation rate, while the C\u00a0&amp;gt;\u00a0G in GCC context is associated with Trp53 mutations. These findings provide new insight into the genetic evolution of chemoresistance, add to emerging evidence that chemotherapeutic agents can produce characteristic mutational signatures, and demonstrate that mutagenic effects of chemotherapy can be indirect, acting through selection of clones with distinct mutation profiles and a resultant mutator phenotype.<\/jats:p>","DOI":"10.1093\/narcan\/zcag017","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:49:44Z","timestamp":1786016984000},"source":"Crossref","is-referenced-by-count":0,"title":["A complex mutational signature generated by cytarabine resistance"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9808-991X","authenticated-orcid":false,"given":"Dengchao","family":"Cao","sequence":"first","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5573-8991","authenticated-orcid":false,"given":"Mianmian","family":"Yin","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson","family":"Lu","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Zhu","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timour","family":"Baslan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, The School of Veterinary Medicine, The University of Pennsylvania , Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang Jo","family":"Chung","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Negi","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0963-1768","authenticated-orcid":false,"given":"Paul","family":"Meltzer","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-9969","authenticated-orcid":false,"given":"Peter D","family":"Aplan","sequence":"additional","affiliation":[{"name":"Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]},{"name":"Myeloid Malignancies Program, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"2026082104371626500_B1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41572-024-00525-x","article-title":"Acute lymphoblastic leukaemia","volume":"10","author":"Pagliaro","year":"2024","journal-title":"Nat Rev Dis Primers"},{"key":"2026082104371626500_B2","doi-asserted-by":"publisher","first-page":"3398","DOI":"10.1172\/JCI61269","article-title":"The molecular basis of T cell acute lymphoblastic leukemia","volume":"122","author":"Van\u00a0Vlierberghe","year":"2012","journal-title":"J Clin Invest"},{"key":"2026082104371626500_B3","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1182\/blood.2019002220","article-title":"Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia","volume":"135","author":"Li","year":"2020","journal-title":"Blood"},{"key":"2026082104371626500_B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2015\/305497","article-title":"Archaeal MCM proteins as an analog for the eukaryotic Mcm2-7 helicase to reveal essential features of structure and function","volume":"2015","author":"Miller","year":"2015","journal-title":"Archaea"},{"key":"2026082104371626500_B5","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1128\/MMBR.00019-09","article-title":"The Mcm complex: unwinding the mechanism of a replicative helicase","volume":"73","author":"Bochman","year":"2009","journal-title":"Microbiol Mol Biol Rev"},{"key":"2026082104371626500_B6","doi-asserted-by":"publisher","first-page":"3121","DOI":"10.1634\/stemcells.2007-0483","article-title":"Reduced Mcm2 expression results in severe stem\/progenitor cell deficiency and cancer","volume":"25","author":"Pruitt","year":"2007","journal-title":"Stem Cells"},{"key":"2026082104371626500_B7","first-page":"3750294","article-title":"MCMs in cancer: prognostic potential and mechanisms","volume":"2020","author":"Yu","year":"2020","journal-title":"Anal Cell Pathol (Amst)"},{"key":"2026082104371626500_B8","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.131434","article-title":"A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia","volume":"4","author":"Yin","year":"2019","journal-title":"JCI Insight"},{"key":"2026082104371626500_B9","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1182\/blood.2018864173","article-title":"Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background","volume":"133","author":"Yin","year":"2019","journal-title":"Blood"},{"key":"2026082104371626500_B10","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/sj.leu.2401997","article-title":"Development and characterization of T cell leukemia cell lines established from SCL\/LMO1 double transgenic mice","volume":"15","author":"Chervinsky","year":"2001","journal-title":"Leukemia"},{"key":"2026082104371626500_B11","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1158\/2159-8290.CD-13-0419","article-title":"NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function","volume":"4","author":"Gough","year":"2014","journal-title":"Cancer Discov"},{"key":"2026082104371626500_B12","article-title":"Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor","volume":"2","author":"Islam","year":"2022","journal-title":"Cell Genom"},{"key":"2026082104371626500_B13","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1101\/gr.188060.114","article-title":"Optimizing sparse sequencing of single cells for highly multiplex copy number profiling","volume":"25","author":"Baslan","year":"2015","journal-title":"Genome Res"},{"key":"2026082104371626500_B14","doi-asserted-by":"publisher","first-page":"6227","DOI":"10.4049\/jimmunol.0901121","article-title":"A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement","volume":"183","author":"Choi","year":"2009","journal-title":"J Immunol"},{"key":"2026082104371626500_B15","doi-asserted-by":"publisher","first-page":"4070","DOI":"10.1128\/MCB.17.7.4070","article-title":"DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis","volume":"17","author":"Stanulla","year":"1997","journal-title":"Mol Cell Biol"},{"key":"2026082104371626500_B16","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.coi.2009.03.009","article-title":"Mechanics of T cell receptor gene rearrangement","volume":"21","author":"Krangel","year":"2009","journal-title":"Curr Opin Immunol"},{"key":"2026082104371626500_B17","doi-asserted-by":"publisher","first-page":"S45","DOI":"10.1016\/S0092-8674(02)00675-X","article-title":"The mechanism and regulation of chromosomal V(D)J recombination","volume":"109 Suppl","author":"Bassing","year":"2002","journal-title":"Cell"},{"key":"2026082104371626500_B18","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1038\/s41416-024-02664-0","article-title":"Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance","volume":"130","author":"Meng","year":"2024","journal-title":"Br J Cancer"},{"key":"2026082104371626500_B19","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s12935-019-0940-9","article-title":"Haploinsufficiency of NR3C1 drives glucocorticoid resistance in adult acute lymphoblastic leukemia cells by down-regulating the mitochondrial apoptosis axis, and is sensitive to Bcl-2 blockage","volume":"19","author":"Xiao","year":"2019","journal-title":"Cancer Cell Int"},{"key":"2026082104371626500_B20","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1172\/JCI130809","article-title":"A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia","volume":"130","author":"Williams","year":"2020","journal-title":"J Clin Invest"},{"key":"2026082104371626500_B21","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65184","article-title":"Transcription-associated topoisomerase 2\u03b1 a (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands","volume":"10","author":"Bossaert","year":"2021","journal-title":"eLife"},{"key":"2026082104371626500_B22","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1038\/s42003-024-07136-y","article-title":"A spectrum of nonsense-mediated mRNA decay efficiency along the degree of mutational constraint","volume":"7","author":"Kim","year":"2024","journal-title":"Commun Biol"},{"key":"2026082104371626500_B23","doi-asserted-by":"publisher","first-page":"5551","DOI":"10.1073\/pnas.0913900107","article-title":"Requirement for deoxycytidine kinase in T and B lymphocyte development","volume":"107","author":"Toy","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026082104371626500_B24","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1159\/000513696","article-title":"Deoxycytidine kinase (DCK) mutations in human acute myeloid leukemia resistant to cytarabine","volume":"144","author":"Wu","year":"2021","journal-title":"Acta Haematol"},{"key":"2026082104371626500_B25","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1182\/blood-2004-03-1046","article-title":"Quantitative analysis of nucleoside transporter and metabolism gene expression in chronic lymphocytic leukemia (CLL): identification of fludarabine-sensitive and -insensitive populations","volume":"105","author":"Mackey","year":"2005","journal-title":"Blood"},{"key":"2026082104371626500_B26","doi-asserted-by":"publisher","first-page":"6217","DOI":"10.1158\/1078-0432.CCR-15-2903","article-title":"Transposon mutagenesis reveals fludarabine resistance mechanisms in chronic lymphocytic leukemia","volume":"22","author":"Pandzic","year":"2016","journal-title":"Clin Cancer Res"},{"key":"2026082104371626500_B27","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nrg3729","article-title":"Mechanisms underlying mutational signatures in human cancers","volume":"15","author":"Helleday","year":"2014","journal-title":"Nat Rev Genet"},{"key":"2026082104371626500_B28","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"2026082104371626500_B29","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/s41375-025-02670-y","article-title":"5-Azacytidine and decitabine induce C &gt;G transversions in both murine and human cells","volume":"39","author":"Bertoli","year":"2025","journal-title":"Leukemia"},{"key":"2026082104371626500_B30","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1158\/0008-5472.CAN-23-2785","article-title":"The DNA methyltransferase inhibitor 5-aza-4'-thio-2'-deoxycytidine induces C&gt;G transversions and acute lymphoid leukemia development","volume":"84","author":"Bertoli","year":"2024","journal-title":"Cancer Res"},{"key":"2026082104371626500_B31","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.1002\/j.1460-2075.1992.tb05500.x","article-title":"The SCL gene product: a positive regulator of erythroid differentiation","volume":"11","author":"Aplan","year":"1992","journal-title":"EMBO J"},{"key":"2026082104371626500_B32","doi-asserted-by":"publisher","first-page":"8956","DOI":"10.1073\/pnas.0803978105","article-title":"Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication","volume":"105","author":"Ibarra","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026082104371626500_B33","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1038\/s41375-024-02403-7","article-title":"Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia","volume":"38","author":"van\u00a0der\u00a0Ham","year":"2024","journal-title":"Leukemia"},{"key":"2026082104371626500_B34","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1101\/gr.242453.118","article-title":"Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans","volume":"29","author":"Zhivagui","year":"2019","journal-title":"Genome Res"},{"key":"2026082104371626500_B35","doi-asserted-by":"publisher","first-page":"4482","DOI":"10.1038\/srep04482","article-title":"Modelling mutational landscapes of human cancers in vitro","volume":"4","author":"Olivier","year":"2014","journal-title":"Sci Rep"},{"key":"2026082104371626500_B36","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1016\/j.ccell.2022.07.002","article-title":"Integrative analysis of drug response and clinical outcome in acute myeloid leukemia","volume":"40","author":"Bottomly","year":"2022","journal-title":"Cancer Cell"},{"key":"2026082104371626500_B37","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/s41589-022-01235-9","article-title":"Etoposide promotes DNA loop trapping and barrier formation by topoisomerase II","volume":"19","author":"Le","year":"2023","journal-title":"Nat Chem Biol"},{"key":"2026082104371626500_B38","doi-asserted-by":"publisher","first-page":"11326","DOI":"10.1074\/jbc.M109.064444","article-title":"Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53\/ARF pathway disruption in spontaneous escape from senescence","volume":"285","author":"Whibley","year":"2010","journal-title":"J Biol Chem"},{"key":"2026082104371626500_B39","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1038\/s41588-024-01785-9","article-title":"Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology","volume":"56","author":"Kinnersley","year":"2024","journal-title":"Nat Genet"},{"key":"2026082104371626500_B40","doi-asserted-by":"publisher","first-page":"e1004585","DOI":"10.1371\/journal.pgen.1004585","article-title":"Hydroxymethylated cytosines are associated with elevated C to G transversion rates","volume":"10","author":"Supek","year":"2014","journal-title":"PLoS Genet"},{"key":"2026082104371626500_B41","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/S1074-5521(01)00019-9","article-title":"Possible cause of G-C\u2192C-G transversion mutation by guanine oxidation product, imidazolone","volume":"8","author":"Kino","year":"2001","journal-title":"Chem Biol"},{"key":"2026082104371626500_B42","doi-asserted-by":"publisher","first-page":"4146","DOI":"10.1093\/nar\/24.21.4146","article-title":"Statistical evidence for a biochemical pathway of natural, sequence-targeted G\/C to C\/G transversion mutagenesis in Haemophilus influenzae Rd","volume":"24","author":"Merkl","year":"1996","journal-title":"Nucleic Acids Res"}],"container-title":["NAR Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/narcancer\/article-pdf\/8\/3\/zcag017\/70743960\/zcag017.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/narcancer\/article-pdf\/8\/3\/zcag017\/70743960\/zcag017.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T08:37:25Z","timestamp":1787301445000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/narcancer\/article\/doi\/10.1093\/narcan\/zcag017\/8767594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,7,27]]}},"URL":"https:\/\/doi.org\/10.1093\/narcan\/zcag017","relation":{},"ISSN":["2632-8674"],"issn-type":[{"value":"2632-8674","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,7,27]]},"article-number":"zcag017"}}