Objective To investigate the expression changes of T-cell exhaustion-related genes in multiple myeloma (MM) and their potential causal relationships.

Methods A bidirectional summary-level Mendelian randomization (MR) analysis was used to explore the causal relationship between T-cell exhaustion and MM. The eQTL data and genome-wide association study (GWAS) were used to summarize data, and corresponding single nucleotide polymorphisms (SNPs) were extracted as instrumental variables. Four methods, namely inverse variance weighted (IVW) method, MR Egger, weighted median, and weighted mode were used to assess the reliability of the causal relationship. The robustness of the results was validated using Cochran′s Q heterogeneity test and pleiotropy test. In cellular models, RNA interference was used to silence key target genes, and phenotypic changes such as myeloma cell viability, colony-forming ability, and apoptosis were observed to experimentally confirm the causal effects revealed by MR.

Results The genes PRDM1, ENTPD1, PTPN11, and HLA-B were involved in the T-cell exhaustion process in MM. The presence of the PRDM1 gene (OR=0.998 5, 95%CI, 0.997 1 to 0.999 8, P=0.024 6) may reduce the risk of MM, whereas ENTPD1 (OR= 1.000 4, 95%CI, 1.000 1 to 1.000 7, P=0.015 8), HLA-B (OR=1.000 4, 95%CI, 1.000 1 to 1.000 8, P=0.012 4), and PTPN11 (OR=1.002 5, 95%CI, 1.001 0 to 1.003 9, P=0.001 2) were associated with an increased risk of MM. Real-time quantitative polymerase chain reaction showed overexpression of PTPN11 in MM cell lines and patients′ samples. By assessing cell viability, colony formation and detecting apoptosis, it was found that inhibiting PTPN11 promoted apoptosis in MM cell lines.

Conclusion A causal relationship exists between T-cell exhaustion and MM. Targeted interventions against specific T-cell exhaustion-related genes may help reduce the incidence of MM.