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While TKIs have improved the prognosis of CML, some patients have shown resistant to therapy. Cases with mutations in epigenome\u2010related genes such as\n                    <jats:italic>ASXL1<\/jats:italic>\n                    are known to have a poor prognosis, but the underlying mechanisms of the poor prognosis are unclear. We showed that mutated\n                    <jats:italic>ASXL1<\/jats:italic>\n                    reduces TKI sensitivity in CML cell lines, and RNA microarray analysis revealed that\n                    <jats:italic>arachidonate 5<\/jats:italic>\n                    \u2010\n                    <jats:italic>lipoxygenase<\/jats:italic>\n                    (\n                    <jats:italic>ALOX5<\/jats:italic>\n                    ) is a significantly upregulated gene under the conditional expression of mutated\n                    <jats:italic>ASXL1<\/jats:italic>\n                    . Enforced\n                    <jats:italic>ALOX5<\/jats:italic>\n                    expression induced TKI resistance, while\n                    <jats:italic>ALOX5<\/jats:italic>\n                    knockout increased TKI sensitivity.\n                    <jats:italic>ALOX5<\/jats:italic>\n                    downstream signal inhibition by LY293111, a leukotriene B4 receptor (BLTR) antagonist, suppressed AKT phosphorylation and enhanced TKI sensitivity. This study revealed that TKI resistance in CML with\n                    <jats:italic>ASXL1<\/jats:italic>\n                    mutation was induced via\n                    <jats:italic>ALOX5<\/jats:italic>\n                    overexpression.\n                    <jats:italic>ASXL1<\/jats:italic>\n                    mutations may confer a clonal advantage through activation of the AKT pathway following\n                    <jats:italic>ALOX5<\/jats:italic>\n                    overexpression. While combined use of LY293111 with TKIs and asciminib showed synergistic effects against CML cells, the ALOX5\u2010BLTR signaling pathway is novel therapeutic target for CML patients with mutated\n                    <jats:italic>ASXL1<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1111\/cas.70007","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T02:04:19Z","timestamp":1738721059000},"page":"1115-1125","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>CML<\/scp>\n                    With Mutant\n                    <scp>ASXL1<\/scp>\n                    Showed Decreased Sensitivity to\n                    <scp>TKI<\/scp>\n                    Treatment via Upregulation of the\n                    <scp>ALOX5<\/scp>\n                    \u2010\n                    <scp>BLTR<\/scp>\n                    Signaling Pathway"],"prefix":"10.1111","volume":"116","author":[{"given":"Naoki","family":"Miyashita","sequence":"first","affiliation":[{"name":"Department of Hematology Hokkaido University Faculty of Medicine, Graduate School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9267-2864","authenticated-orcid":false,"given":"Masahiro","family":"Onozawa","sequence":"additional","affiliation":[{"name":"Department of Hematology Hokkaido University Faculty of Medicine, Graduate School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Department of Hematology Hokkaido University Faculty of Medicine, Graduate School of Medicine  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiro","family":"Matsukawa","sequence":"additional","affiliation":[{"name":"Department of Hematology 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