Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Nat Commun. 2024 Nov 22;15(1):10131. doi: 10.1038/s41467-024-54571-w.
The RVd therapy, combining lenalidomide, bortezomib, and dexamethasone, is a mainstay treatment for multiple myeloma. A multiple myeloma patient developed pure red cell aplasia (PRCA) following RVd treatment, despite the absence of common PRCA triggers. In vitro analyses reveal lenalidomide as a pivotal disruptor of erythropoiesis. Single-cell transcriptome analysis unveils hyperactive CD8 T cells and impaired erythropoiesis in the patient's bone marrow. Unexpectedly, the patient's erythroid cells display abnormally high expression of genes in the antigen presentation pathway, particularly those for major histocompatibility class I (MHC-I) molecules. Functional assays demonstrate that lenalidomide treatment further augmented MHC-I expression in the patient's erythroid cells. Blocking MHC-I or depleting T cells alleviates the defective erythropoiesis of PRCA, suggesting that the interaction between erythroid cells with elevated MHC-I and T cells in the bone marrow might contribute to PRCA. Taken together, our study implicates a mechanism underlying lenalidomide-induced PRCA in treating cancer patients.
RVd 疗法联合来那度胺、硼替佐米和地塞米松是多发性骨髓瘤的主要治疗方法。一名多发性骨髓瘤患者在接受 RVd 治疗后出现纯红细胞再生障碍性贫血（PRCA），尽管没有常见的 PRCA 触发因素。体外分析显示来那度胺是红细胞生成的关键破坏者。单细胞转录组分析揭示了患者骨髓中 CD8+T 细胞过度活跃和红细胞生成受损。出乎意料的是，患者的红细胞异常高表达抗原呈递途径中的基因，特别是主要组织相容性复合体 I（MHC-I）分子的基因。功能分析表明，来那度胺治疗进一步增强了患者红细胞中 MHC-I 的表达。阻断 MHC-I 或耗尽 T 细胞可缓解 PRCA 的红细胞生成缺陷，表明骨髓中高表达 MHC-I 的红细胞与 T 细胞之间的相互作用可能导致 PRCA。总之，我们的研究提示了来那度胺治疗癌症患者引起 PRCA 的一种机制。
