Recently, Yijun Chen/Yong Yang/Can Zhang/Shuzhen Wang's group collaborated to publish the research results of target discovery and gene therapy for Philadelphia chromosome-positive (Ph+) leukemia in the international academic journals eLife (CAS 1, Top) and Journal of Nanobiotechnology (CAS 1, Top), with the Chinese University of Pharmacy and Pharmaceutical Sciences (CUPT) being the The first unit.
Ph+ leukemia is a highly lethal hematologic malignancy caused by the expression of BCR-ABL fusion proteins, which gave birth to the first molecularly targeted drug imatinib from the perspective of inhibiting its tyrosine protein kinase activity. Although several tyrosine kinase inhibitors already on the market can significantly improve the prognosis and effectively prolong the survival of patients with Ph+ leukemia, relapse, susceptibility to drug resistance, and patient intolerance are still urgent clinical problems that need to be solved, and new therapeutic strategies are urgently needed. To address these problems, from the regulatory mechanism of BCR-ABL protein stability, it was found that the backbone protein RAPSYN mediated the neddylation post-translational modification of BCR-ABL protein through its NEDD8 E3 ligase function, and this modification formed a barrier on the surface of this oncoprotein, which prevented c-CBL E3 ligase-mediated ubiquitylated protein degradation, enhanced This modification formed a barrier on the surface of the oncoprotein, preventing c-CBL E3 ligase-mediated degradation of ubiquitinated proteins and enhancing the stability and half-life of the BCR-ABL protein, which in turn facilitated the disease onset and progression. The research results were published as “RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia “Dr. Zhao Menya, Associate Researcher Dai Beiying, Ph.D. student Li Xiaodong and Ph.D. student Zhang Yixin are the co-first authors of this paper, and Prof. Chen Yijun, Prof. Yang Yong and Associate Prof. Wang Shuzhen are the co-corresponding authors of this paper.
Link to the paper: https://elifesciences.org/reviewed-preprints/88375
Then, for the novel target of RAPSYN, the single-chain antibody fragment anti-CD79B-scFv was coupled to the surface of nano-lipid particles, and then encapsulated to deliver siRAPSYN, which specifically silenced the RAPSYN gene, inhibited the Neddylation modification of the BCR-ABL protein, and achieved the effective degradation of BCR-ABL, thus exerting the role of inhibiting the development of Ph+ leukemia development and substantially prolonged the survival of leukemia model animals. In particular, by applying CD79B single-chain antibody fragments, we have achieved the selective targeting of myeloid leukemia cells in the circulatory system, and have effectively improved the durability of RAPSYN, which is a target that exists in a wide range of tissues. The research results were published under the title of “Targeted Degradation of Oncogenic BCR-ABL by Silencing the Gene of NEDD8 E3 Ligase RAPSYN”, and Dr. Yanzhi Sun was the first author of this paper. Dr. Yanzi Sun is the first author of this paper, and Prof. Yijun Chen, Prof. Can Zhang and Associate Researcher Yun Cao Ju are the co-corresponding authors.
Link: https://doi.org/10.1186/s12951-024-02505-5
The above study not only elucidated the close relationship between RAPSYN and neddylation modification of BCR-ABL as well as the development of Ph+ leukemia, but also provided a new strategy of gene therapy for the treatment of TKI-resistant Ph+ leukemia.
The above work was supported by the National Key Research and Development Program of China (2018YFA0902000), the National Natural Science Foundation of China (81872924, 82002971), the National Key Laboratory of Multi-target Natural Medicines (SKLNMZZ202201), and the “Dual First-class Universities” project of the China Pharmaceutical University (CPU20202201). The project of “Double First-class University” of China Pharmaceutical University (CPU2022QZ014) was funded by the National Natural Science Foundation of China.
