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Ph+ ALL shows a high incidence of\n                    <jats:italic>IKZF1<\/jats:italic>\n                    deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of\n                    <jats:italic>IKZF1<\/jats:italic>\n                    , encoding protein IKAROS, contributes to its dysfunction, and CK2 inhibitor, CX-4945, restores IKAROS function in high-risk ALL. Here, we found that Ph+ ALL cells with\n                    <jats:italic>IKZF1<\/jats:italic>\n                    deletion are inherently resistant to TKIs. The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the\n                    <jats:italic>IKZF1<\/jats:italic>\n                    deletion (Ik6\n                    <jats:sup>+<\/jats:sup>\n                    ) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19\/CD3 bispecific antibody blinatumomab.\n                    <jats:italic>GLUT1<\/jats:italic>\n                    is highly expressed in the Ph+ ALL and associated with synergy of TKIs with CX-4945; Seahorse assay showed enhanced glycolysis in the patient sample with Ik6\n                    <jats:sup>+<\/jats:sup>\n                    Ph+ ALL;\n                    <jats:italic>GLUT1<\/jats:italic>\n                    knockdown suppresses glycolysis and induces apoptosis in the cells. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of\n                    <jats:italic>GLUT1<\/jats:italic>\n                    and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02898-2","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T08:19:46Z","timestamp":1772785186000},"page":"794-805","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing tyrosine kinase inhibitor sensitivity by restoring IKAROS activity on GLUT1 expression and glycolysis in Philadelphia chromosome-positive acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"40","author":[{"given":"Linyao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6916-9400","authenticated-orcid":false,"given":"Rosa","family":"Lapalombella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6442-1419","authenticated-orcid":false,"given":"Ann-Kathrin","family":"Eisfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-6877","authenticated-orcid":false,"given":"Walter G.","family":"Hanel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan E.","family":"Brammer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-2199","authenticated-orcid":false,"given":"Alice S.","family":"Mims","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3403-9144","authenticated-orcid":false,"given":"Jennifer A.","family":"Woyach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-2543","authenticated-orcid":false,"given":"Chunhua","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-1612","authenticated-orcid":false,"given":"Zheng","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"2898_CR1","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1002\/cncr.29383","volume":"121","author":"E Jabbour","year":"2015","unstructured":"Jabbour E, O\u2019Brien S, Konopleva M, Kantarjian H. 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