BACKGROUND: The complicated autoimmune disease known as systemic lupus erythematosus (SLE) is characterized by abnormal immunological B cell modulation that exhibits enhanced survival. The genes Tp53, MDM2, and CDKN2A (ARF) play crucial roles in cellular regulation. In this study, we aim to elucidate the status of these genes. This might be a factor in the B cells' higher survival rate in SLE. METHODS: B cells were obtained from the peripheral blood of participants and cultured, with a subset of the cells activated using anti-IgM. The expression levels of Tp53, MDM2, and CDKN2A genes were assessed both at baseline and after activation. RESULTS: Tp53 and CDKN2A exhibited decreased expression in both baseline and activated B cells, with further decreases observed active and inactive SLE. Conversely, MDM2 demonstrated increased expression in baseline B cells, with a more pronounced increase observed in activated B cells of active SLE. Correlation analysis indicated several significant positive and negative associations, particularly between disease activity indicators and MDM2 expression, as well as among the studied genes. CONCLUSION: The dysregulation of the CDKN2A-MDM2-p53 axis in B cells of SLE may lead to increased B cell survival due to reduced Tp53 and CDKN2A expression and elevated MDM2 levels. In addition, MDM2 gene expression levels show a significant positive correlation with disease activity indices like anti-dsDNA titer and SLEDAI score in SLE patients.