{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:50:50Z","timestamp":1747183850908,"version":"3.40.5"},"reference-count":36,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,6,14]],"date-time":"2020-06-14T00:00:00Z","timestamp":1592092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To elucidate dynamic changes in native <jats:italic>BCR\u2010ABL<\/jats:italic> and alternatively spliced tyrosine kinase inhibitor (TKI)\u2010resistant but function\u2010dead <jats:italic>BCR\u2010ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic> variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such <jats:italic>BCR\u2010ABL<\/jats:italic> variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic>, accounting for 0.8% of the total IS <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<\/jats:italic>, corresponding to actual <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic> value of 1.1539% IS. TKI rapidly decreased native <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<\/jats:italic> but not <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic>, leading to the initial increase in the proportion of <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic>. Thereafter, both native <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<\/jats:italic> and <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic> gradually decreased in the course of TKI treatment, whereas small populations positive for TKI\u2010resistant <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic> continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<\/jats:italic><jats:sup>+<\/jats:sup> clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function\u2010dead <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic>, suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis\u2010splicing <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic>, occurring at the particular pseudo\u2010splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<\/jats:italic> extracting <jats:italic>BCR<\/jats:italic>\u2010<jats:italic>ABL<jats:sup>Ins35bp<\/jats:sup><\/jats:italic> would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.<\/jats:p>","DOI":"10.1111\/cas.14424","type":"journal-article","created":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T07:40:30Z","timestamp":1587454830000},"page":"2361-2373","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tyrosine kinase inhibitors induce alternative spliced <i>BCR\u2010ABL<\/i><sup>Ins35bp<\/sup> variant via inhibition of RNA polymerase II on genomic BCR\u2010ABL"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-1636","authenticated-orcid":false,"given":"Junichiro","family":"Yuda","sequence":"first","affiliation":[{"name":"Department of Medicine and Biosystemic Science Kyushu University Graduate School of Medical Science Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Odawara","sequence":"additional","affiliation":[{"name":"Department of Medicine and Biosystemic Science Kyushu University Graduate School of Medical Science Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariko","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Medicine and Biosystemic Science Kyushu University Graduate School of Medical Science Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Muta","sequence":"additional","affiliation":[{"name":"Department of Hematology 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