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Inhibition of Tumoral VISTA to Overcome TKI Resistance via Downregulation of the AKT/mTOR and JAK2/STAT5 Pathways in Chronic Myeloid Leukemia.
Ai, Kexin; Chen, Mu; Liang, Zhao; Ding, Xiangyang; Gao, Yang; Zhang, Honghao; Wu, Suwan; He, Yanjie; Li, Yuhua.
Afiliación
  • Ai K; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Chen M; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Liang Z; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Ding X; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Gao Y; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Zhang H; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Wu S; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • He Y; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • Li Y; Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
Biomol Ther (Seoul) ; 32(5): 582-600, 2024 Sep 01.
Article en En | MEDLINE | ID: mdl-39104205
ABSTRACT
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCRABL1-dependent and BCRABL1-independent pathways. The mechanisms underlying BCRABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCRABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/ mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCRABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCRABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomol Ther (Seoul) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación:
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Biomol Ther (Seoul) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: