Lenalidomide-induced pure red cell aplasia is associated with elevated expression of MHC-I molecules on erythrocytes

• Published in: Nature communications Vol. 15; no. 1; pp. 10131 - 13
• Main Authors: Hu, Qi, Liu, Yang, Yue, Qiuyu, Zhou, Shuo, Jin, Xianghong, Lin, Fan, Huang, Xiao-Jun, Zhuang, Junling, Lu, Jin, Gao, Xiaofei, Lee, Hsiang-Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.11.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 38/39; 631/250/1619/554/1834/1269; 631/250/21/324/1509; 631/250/2502; 692/4017; 692/699/1541; Antigen presentation; Antigens; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aplasia; Bone cancer; Bone marrow; Bone Marrow - drug effects; Bone Marrow - pathology; Bortezomib; Bortezomib - pharmacology; Bortezomib - therapeutic use; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - metabolism; Erythroid cells; Erythropoiesis; Erythropoiesis - drug effects; Genes; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humanities and Social Sciences; Humans; Immunotherapy; Inhibitor drugs; Lenalidomide - pharmacology; Lenalidomide - therapeutic use; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; multidisciplinary; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Patients; Red-Cell Aplasia, Pure - chemically induced; Red-Cell Aplasia, Pure - drug therapy; Science; Science (multidisciplinary); Single-Cell Analysis; Targeted cancer therapy; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• 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. On rare occasions, some multiple myeloma patients develop pure red cell aplasia (PRCA) following combination therapy for multiple myeloma. Here the authors characterise bone marrow cells from PRCA patients by single cell sequencing showing hyperactive CD8 + T cells, impaired erythropoiesis, increase of MHC-I proteins and antigen presentation associated genes in erythroid cells.