{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T20:14:06Z","timestamp":1783455246497,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["5\/13\/19\/PB\/ICRC\/2022\/NCD\u2010III"],"award-info":[{"award-number":["5\/13\/19\/PB\/ICRC\/2022\/NCD\u2010III"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>\n                    Acquired thiopurine resistance and mismatch repair (MMR) deficiency are increasingly recognised drivers of relapse in paediatric B\u2010cell acute lymphoblastic leukaemia (B\u2010ALL); however, their real\u2010world genomic prevalence and link to maintenance dosing patterns remain poorly characterised. Paediatric B\u2010ALL relapse cases (2018\u20132024) were subjected to whole exome sequencing (WES; 200\u2013250\u00d7 depth;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200970) and deep targeted sequencing (700\u2013900\u00d7;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20095). Per\u2010sample frequencies of resistance gene mutations, single\u2010base mutational signatures, tumour mutational burden\u2010high (\u226510 mutations\/Mb), microsatellite instability\u2010high (MSI\u2010H) and thiopurine S\u2010methyltransferase\u00a0(\n                    <jats:italic>TPMT)\/nucleoside diphosphate\u2010linked moiety X\u2010type motif 15 (NUDT15)<\/jats:italic>\n                    status were determined. Clinical variables included the median weekly 6\u2010mercaptopurine (6\u2010MP) dose (mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    , time\u2010weighted) and duration of 6\u2010MP dose interruptions. A total of 18\/75 (24%) relapse cases showed SBS87 (thiopurine\u2010related), SBS6\/15 (MMR\u2010related) or Thio\u2010deficient mismatch repair (Thio\u2010dMMR) mutational signature. Thiopurine resistance clones in cytosolic 5'\u2010nucleotidase II (\n                    <jats:italic>NT5C2)<\/jats:italic>\n                    (13), phosphoribosyl pyrophosphate synthetase 1 (\n                    <jats:italic>PRPS1)<\/jats:italic>\n                    (2) or tumor protein p53 (\n                    <jats:italic>TP53)<\/jats:italic>\n                    (7) were noted in 19\/75 (25%) cases; germline or somatic clones in MMR genes were noted in 19\/75 (25%). Correlation analysis revealed that both low median weekly 6\u2010MP dose (&lt;45\u2009mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    ) and \u22654\u2009weeks of dose interruptions were significantly associated with higher hazard for SBS87 or Thio\u2010dMMR signature (hazard ratio [HR] 7.09 [95% confidence interval (CI): 1.77\u201328.34],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.006, and HR 6.21 [95% CI: 1.66\u201323.32],\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.007 respectively). This real\u2010world study demonstrates that suboptimal median 6\u2010MP dosing and prolonged dose interruptions during maintenance are significantly associated with thiopurine resistance and MMR deficiency\u2010related mutational signatures at relapse. These findings underscore the importance of optimised dose intensity and minimal interruptions during maintenance therapy in paediatric B\u2010ALL.\n                  <\/jats:p>","DOI":"10.1111\/bjh.70560","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T14:29:13Z","timestamp":1779805753000},"page":"54-62","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acquired thiopurine resistance and mismatch repair aberrations in paediatric B\u2010cell acute lymphoblastic leukaemia relapse: A real\u2010world data integrating mutational signatures, clones and clinical thiopurine dosing patterns"],"prefix":"10.1111","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-3587","authenticated-orcid":false,"given":"Prateek","family":"Bhatia","sequence":"first","affiliation":[{"name":"Pediatric Hematology\u2010Oncology Unit, Department of Pediatrics PGIMER  Chandigarh 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