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<p>Many patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are still less sensitive to tyrosine kinase inhibitors (TKIs). Ph+ ALL shows a high incidence of <i>IKZF1</i> deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of <i>IKZF1</i>, 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 <i>IKZF1</i> 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 <i>IKZF1</i> deletion (Ik6<sup>+</sup>) 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. <i>GLUT1</i> 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<sup>+</sup> Ph+ ALL; <i>GLUT1</i> 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 <i>GLUT1</i> 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.</p>

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Enhancing tyrosine kinase inhibitor sensitivity by restoring IKAROS activity on GLUT1 expression and glycolysis in Philadelphia chromosome-positive acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Linyao Zhang,
  • Qi Han,
  • Huimin Xiang,
  • Rosa Lapalombella,
  • Ann-Kathrin Eisfeld,
  • Walter G. Hanel,
  • Jonathan E. Brammer,
  • Alice S. Mims,
  • Jennifer A. Woyach,
  • Chunhua Song,
  • Zheng Ge

摘要

Many patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are still less sensitive to tyrosine kinase inhibitors (TKIs). Ph+ ALL shows a high incidence of IKZF1 deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of IKZF1, 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 IKZF1 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 IKZF1 deletion (Ik6+) 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. GLUT1 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+ Ph+ ALL; GLUT1 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 GLUT1 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.