GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia
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- GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia
- Han, Seung Hun; Korm, Sovannarith; Han, Ye Gi; Choi, Soo-Young; Kim, Soo-Hyun; Chung, Hee Jin; Park, Kibeom; Kim, Jae-Young; Myung, Kyungjae; Lee, Joo-Yong; Kim, Hongtae; Kim, Dong-Wook
- Issue Date
- TAYLOR & FRANCIS INC
- AUTOPHAGY, v.15, no.12, pp.2076 - 2090
- Imatinib is the first molecularly targeted compound for chronic myeloid leukemia (CML) capable to inhibit BCR-ABL kinase activity. However, recent clinical evidence indicates that a substantial proportion of CML patients exhibit BCR-ABL-dependent or independent resistance to imatinib. Despite the importance of imatinib resistance in CML, the underlying molecular mechanisms of this resistance are largely unknown. Here, we identified GCA (grancalcin) as a critical regulator of imatinib resistance in chronic phase CML via activation of autophagy. Mechanistically, we demonstrated that GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. We also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. Our findings represent the basis for novel therapeutic strategies against CML.
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