{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:15:21Z","timestamp":1791321321816,"version":"4.3.1"},"reference-count":50,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Osteonecrosis and fractures are serious corticosteroid\u2010induced bone toxicities in children treated for acute lymphoblastic leukemia, yet their genetic determinants remain incompletely defined. In this study, we aimed to identify novel genetic contributors to bone toxicity and to evaluate the robustness of both newly identified and previously established risk genotypes in more recent Dana\u2010Farber Cancer Institute treatment protocols. Whole\u2010exome sequencing was first performed in a discovery cohort to identify genetic variants associated with osteonecrosis. A novel association with a variant in the\n                    <jats:italic>PGAP2<\/jats:italic>\n                    gene was identified and subsequently confirmed in an independent replication cohort, with effects of patient\u2010 and disease\u2010related characteristics observed in both cohorts. Next, previously reported candidate gene\u2013derived associations, together with this newly identified variant, were assessed in a more recent cohort to examine their relevance in contemporary treatment protocols. Variants in\n                    <jats:italic>BCL2L11<\/jats:italic>\n                    and the\n                    <jats:italic>ACP1\u2013SH3YL1<\/jats:italic>\n                    locus were associated with bone fractures, with a strong synergistic effect and significant modulation by protocol\u2010specific factors, particularly corticosteroid exposure and asparaginase formulation. The\n                    <jats:italic>PGAP2<\/jats:italic>\n                    variant was associated with the combined osteonecrosis\u2010fracture phenotype. Transcriptomic analyses revealed isoform\u2010specific expression shifts in\n                    <jats:italic>PGAP2<\/jats:italic>\n                    in patients with osteotoxicity, supporting a potential functional role for altered splicing or gene regulation. Together, our results provide insight into the pharmacogenomic architecture of osteotoxicity in ALL, demonstrating that\n                    <jats:italic>PGAP2<\/jats:italic>\n                    ,\n                    <jats:italic>BCL2L11<\/jats:italic>\n                    , and\n                    <jats:italic>ACP1\u2013SH3YL1<\/jats:italic>\n                    variants remain clinically relevant predictors of bone toxicity across evolving treatment protocols. However, their clinical manifestations appear to be context\u2010dependent, underscoring the importance of integrating genetic susceptibility with pharmacologic exposures and supporting further investigation of the underlying molecular mechanisms.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70371","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T09:06:37Z","timestamp":1782119197000},"page":"786-794","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic Determinants of Treatment\u2010Related Bone Toxicity in Pediatric Acute Lymphoblastic Leukemia"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7417-3575","authenticated-orcid":false,"given":"Rachid","family":"Abaji","sequence":"first","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center, CHU Sainte\u2010Justine Research Center  Montreal Qu\u00e9bec Canada"},{"name":"Department 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Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Del Vecchio","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center, CHU Sainte\u2010Justine Research Center  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"Ait Said","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center, CHU Sainte\u2010Justine Research Center  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Shalmiev","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center, CHU Sainte\u2010Justine Research Center  Montreal Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center, CHU Sainte\u2010Justine Research Center  Montreal Qu\u00e9bec 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Accessed July 21 2025."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70371","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70371","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70371","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T20:35:51Z","timestamp":1785962151000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70371"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/cpt.70371"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70371","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"assertion":[{"value":"2026-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}