We conducted a retrospective study in which the clinical features of 67 patients with PCNSL were evaluated, both with and without HIV infection. PCNSL can occur in any part of the CNS but is most often found in the supratentorial region. The sites at which the tumor occurred were not significantly different between HIV-related PCNSL and IC-PCNSL. The age and gender distribution of the patients with HIV-related PCNSL were in line with previous findings, with younger male patients being more common than younger patients with IC-PCNSL [9]. HIV-related PCNSL patients were more likely to have elevated LDH, CSF protein, and CSF chloride levels and lower CSF sugar. This could be because PCNSL patients can disseminate through the cerebrospinal fluid [10], and HIV-related PCNSL patients are more prone to spread through the cerebrospinal fluid.
Histologically, 25 of the 37 HIV-related PCNSL patients (67.6%) overexpressed of the protein Bcl-2, which is basically consistent with the literature (40%-81%) [11]. Among the IC-PCNSL patients, only 23.3% had Bcl-2 overexpression, this may be because the Bcl-2 protein is a cell apoptosis inhibitor gene and an important pathogenic factor in the development of lymphoma. Our study revealed that 86.5% of the patients had high Ki-67 expression (Ki-67 index > 50%), which is consistent with the literature and indicates rapid growth of tumor cells [12]. Reis et al. [13] reported that increased expression of Bcl-6 in patients with PCNSL was associated with an extended period of survival, indicating its predictive value. Therefore, the lower expression of Bcl-6 in HIV-related PCNSL may indicate a poorer prognosis than in IC-PCNSL. The TP53 gene is one of the most important tumor suppressor genes and regulates the cell cycle, apoptosis, and repair of DNA damage [14]. Our research revealed that p53 expression was significantly increased in HIV-related PCNSL. In addition, we conducted EBER in situ hybridization and found that 81.1% of the HIV-related PCNSL patients tested positive for EBER. No patients with IC-PCNSL were found to have EBV. EBV infection in humans could play a significant role in causing immunodeficiency among patients diagnosed with PCNSL [15]. In addition to EBV infection immortalizing normal B cells, infected B cells can also escape suppression by normal T cells, leading to malignant transformation [16].
However, the pathogenesis of PCNSL is still unclear. Current research suggests that changes in epigenetic modifications are closely related to the onset of PCNSL [17]. In eukaryotic cells, m6A modification is an important form of epigenetic modification, and plays a crucial regulatory role in cell differentiation, the stress response, tumor formation, and correlation with virus infection. The abundance of m6A in both viral and host-cell RNA is significantly increased by HIV infection [18]. This fact motivates further exploration of the involvement of RNA methylation in HIV biology and the mammalian response to viral infection. m6A modification is regulated mainly by complex interactions between methyltransferase complexes, demethylases, and methylation-reading proteins. Some of the members of the methyltransferase complex are METTL3, METTL14, METTL16, Wilms tumor 1-associated protein, RNA binding motif protein 15, and KIAA1429 [19]. Mounting evidence shows that the abnormal expression and function of METTL3 are closely related to tumor progression. Mechanistically, METTL3 can promote the translation of MYC, Bcl-2 and PTEN mRNAs. METTL3 can also regulate the stability of mRNAs by changing the level of m6A modification [20]. Therefore, further research on the role and specific molecular mechanism of METTL3 in HIV-related PCNSL development is highly important, and it is anticipated that HIV-related PCNSL will offer novel molecular targets for clinical diagnosis and treatment. We found that 84.6% of the HIV-related PCNSL patients exhibited high METTL3 expression, and in the IC-PCNSL cohort, only 43.4% of the patients exhibited high METTL3 expression. Therefore, we can infer that the HIV virus may cause excessive levels of m6A through promoting the expression of METTL3, leading to changes in the expression of downstream genes, such as Bcl-2, p53, and Bcl-6, as well as other genetic abnormalities; dysregulation and release of cytokines; damage to dendritic cells; and/or infection with EB virus, hepatitis C virus, or other viruses. These stimuli lead to rearrangement of immunoglobulin variable genes, ultimately leading to the development of HIV-related PCNSL. Therefore, compared to patients with IC-PCNSL, patients with HIV-related PCNSL have earlier disease onset and a worse prognosis.
In addition, HIV-related PCNSL patients with ABC-like DLBCL were more likely to express METTL3 than were those with GCB-like DLBCL. This may indicate that in HIV-related PCNSL, the expression of METTL3 not only promotes the occurrence and progression of PCNSL but also may be related to the origin of the tumor cells. Earlier studies have reported that compared to ABC-like DLBCL, GCB-like DLBCL has a better prognosis [21], therefore, there may be a correlation between the expression of METTL3 and the prognosis of HIV-related PCNSL.