<scp>CML</scp> With Mutant <scp>ASXL1</scp> Showed Decreased Sensitivity to <scp>TKI</scp> Treatment via Upregulation of the <scp>ALOX5</scp>‐<scp>BLTR</scp> Signaling Pathway

In this study, the mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) were investigated focusing additional sex combs-like 1 (ASXL1) gene mutations and their downstream effects. While TKIs have improved the prognosis of CML, some patients have shown resistant to therapy. Cases with mutations in epigenome-related genes such as ASXL1 are known to have a poor prognosis, but the underlying mechanisms of the poor prognosis are unclear. We showed that mutated ASXL1 reduces TKI sensitivity in CML cell lines, and RNA microarray analysis revealed that arachidonate 5-lipoxygenase (ALOX5) is a significantly upregulated gene under the conditional expression of mutated ASXL1. Enforced ALOX5 expression induced TKI resistance, while ALOX5 knockout increased TKI sensitivity. ALOX5 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 ASXL1 mutation was induced via ALOX5 overexpression. ASXL1 mutations may confer a clonal advantage through activation of the AKT pathway following ALOX5 overexpression. While combined use of LY293111 with TKIs and asciminib showed synergistic effects against CML cells, the ALOX5-BLTR signaling pathway is novel therapeutic target for CML patients with mutated ASXL1.