靶向SETD2-H3K36me3通过调控BCMA/CD56增效CD56 CAR-T治疗复发难治性多发性骨髓瘤

尽管CAR-T是RRMM重要挽救策略，但受限于靶抗原下调/缺失，再复发不可避免。探索可杀伤肿瘤并诱导靶抗原表达增效CAR-T的药物是RRMM的前沿方向。组蛋白甲基转移酶异常表达所致转录调控失衡可促进MM发生发展。以H3K36me3唯一酶SETD2在MM检出高频突变为切入点，我们发现SETD2低表达MM患者危险度高、分期晚、预后差，敲降SETD2可加快MM细胞增殖及周期进程，H3K36me3去甲基酶抑制剂具体外抗MM作用。BCMA和CD56是识别MM的重要抗原，已证实CD56 CAR-T可有效治疗MM，而对侵袭强、预后差的CD56-MM无效。应用转录组测序我们发现SETD2在MM细胞中可下调BCMA、上调CD56。由此提出，应用靶向药物提高MM细胞H3K36me3，通过调控BCMA/CD56，发挥杀肿瘤并增效CD56 CAR-T抗MM效应这一假说并论证，为维持RRMM长期深度缓解提供新思路。

Although CAR-T cell therapy is an important rescue strategy for the relapsed or refractory multiple myeloma (RRMM), the recurrence of RRMM is inevitable due to the downregulation or deletion of target antigen in myeloma cells. Exploring targeted drugs that could kill tumors and induce the expression of target antigen to enhance the efficacy of CAR-T therapy simultaneously is the frontier research of RRMM. Abnormal expression of histone methyltransferases could result in unbalanced transcription regulation, which promotes the occurrence and progression of MM. In the study of SETD2, the only enzyme of H3K36me3 with high frequency mutations in MM, we found that MM patients with low expression of SETD2 have a higher disease risk, later ISS stage and poorer prognosis, and knocking down of SETD2 could accelerate the proliferation and cell cycle of MM cells. The H3K36me3 demethylase inhibitor exhibits anti-myeloma effects in vitro. BCMA and CD56 are the important tumor antigens of MM. It has been demonstrated that CD56 CAR-T therapy is effective in eradicating tumor cells in MM patients, but spares no effort to CD56-MM patients characterized by a strong invasion and poor prognosis. Using transcriptome sequencing, we found that SETD2 can down-regulate the expression of BCMA and up-regulate the expression of CD56. Therefore, we propose and will demonstrate that the application of targeted drugs improves the level of H3K36me3 in MM cells, and thus regulates the expression of BCMA/CD56, can kill tumor cells and enhance the anti-myeloma effect of CD56 CAR-T therapy. Completing this project will provide new ideas for achieving the deep durable remissions of RRMM.