GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia
GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia
复制标题
DOI：
10.1080/15548627.2019.1596492
复制
发表时间：
2019-04-01
期刊：
影响因子：
13.3
通讯作者：
Kim, Dong-Wook
中科院分区：
文献类型：
--
作者：
Han, Seung Hun;Korm, Sovannarith;Kim, Dong-Wook
伊马替尼是第一个能够抑制BCR-ABL激酶活性的慢性粒细胞白血病（CML）分子靶向化合物。然而，最近的临床证据表明，相当一部分CML患者表现出BCR-ABL依赖性或独立的耐药性伊马替尼。尽管伊马替尼耐药在CML中的重要性，但这种耐药的潜在分子机制在很大程度上是未知的。在这里，我们确定GCA（grancalcin）作为伊马替尼耐药的慢性期CML通过激活自噬的关键调节剂。从机制上讲，我们证明了GCA激活TRAF6泛素连接酶活性以诱导ULK1的Lys63泛素化，ULK1是自噬的关键调节因子，导致其稳定和激活。我们还强调了GCA-TRAF6-ULK1自噬调节轴在伊马替尼耐药中的作用。我们的研究结果代表了针对CML的新治疗策略的基础。
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.