Zhang Lu, Wang Xuefeng, Hu Dongmei, Li Shijie, Sun Mingshan, Liu Qian, Feng Huimin, Zhou Minran, Chen Chunyan, Zhou Huan, Ma Sai
Department of Hematology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, China.
National Drug Clinical Trial Institution, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Oncogene. 2025 Mar 27. doi: 10.1038/s41388-025-03350-y.
Tyrosine kinase inhibitors (TKIs) targeting the oncoprotein BCR-ABL have improved the prognosis for patients with chronic myeloid leukemia (CML). However, TKI resistance and persistent expression of BCR-ABL are responsible for the relapse and progression of CML. Here, we describe a novel approach to induce BCR-ABL protein degradation by small ubiquitin-like modifier (SUMO) modification. The E3 SUMO ligase TRIM28, upregulated during the progression of CML, promoted SUMOylation of BCR-ABL, thereby inhibiting its binding to the autophagy receptor P62 and repressing its autophagic degradation. Accordingly, genetic and pharmacological inhibition of TRIM28 or SUMOylation suppressed progression in both the CML mouse model and patient-derived xenograft model. Furthermore, targeting SUMOylation of BCR-ABL restrained the proliferation of TKI-resistant CML cells. These results identify the mechanism by which TRIM28 maintains BCR-ABL stability to promote CML progression and suggest SUMOylation as a target for CML treatment.
靶向癌蛋白BCR-ABL的酪氨酸激酶抑制剂（TKIs）改善了慢性粒细胞白血病（CML）患者的预后。然而，TKI耐药以及BCR-ABL的持续表达是CML复发和进展的原因。在此，我们描述了一种通过小泛素样修饰物（SUMO）修饰诱导BCR-ABL蛋白降解的新方法。E3 SUMO连接酶TRIM28在CML进展过程中上调，促进了BCR-ABL的SUMO化，从而抑制其与自噬受体P62的结合并抑制其自噬降解。因此，对TRIM28或SUMO化的基因和药物抑制在CML小鼠模型和患者来源的异种移植模型中均抑制了疾病进展。此外，靶向BCR-ABL的SUMO化抑制了TKI耐药CML细胞的增殖。这些结果确定了TRIM28维持BCR-ABL稳定性以促进CML进展的机制，并表明SUMO化可作为CML治疗的靶点。
