BackgroundCD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) showed poor prognosis in the rituximab era, with limited research on its genetic characteristics and cell of origin (COO). We aimed to demonstrate the molecular characteristics of CD5+ DLBCL and to discover potential prognostic factors.MethodsWe included 24 cases of CD5+ DLBCL and 23 CD5-negative (CD5-) counterparts and collected their clinicopathological features. Targeted DNA sequencing of 475 lymphoma-related genes was performed, and all cases were assigned to distinct genetic subtypes using the LymphGen tool. The COO was determined by the Lymph2Cx assay. The Kaplan–Meier method and Cox proportional hazards model were applied to identify the possible prognostic factors.ResultsCompared with their CD5- counterparts, patients with CD5+ DLBCL tended to have a worse prognosis and a higher incidence of MYD88L265P and CD79B double mutation (MCD) subtype (54.17%, P = 0.005) and activated B cell-like (ABC) subtype (62.5%, P = 00017), as determined by next-generation sequencing and Lymph2Cx, respectively. Moreover, PIM1, MYD88, and KMT2D mutations were detected more frequently in CD5+ DLBCL cases (P < 0.05). According to multivariate analysis, MYC/BCL2 double expression and ABC subtype were correlated with unfavorable overall survival (OS). High mRNA expression of SERPINA9 and MME showed a significant correlation with a better OS, and high expression of MME showed a significant correlation with better progression-free survival in CD5+ DLBCL.ConclusionThe genetic profile of CD5+ DLBCL is characterized by PIM1, MYD88, and KMT2D mutations, with a higher incidence of MCD and ABC subtypes. MYC/BCL2 double expression, ABC subtype, and mRNA expression of SERPINA9 and MME are independently predictive of the prognosis of CD5+ DLBCL.
De novo CD5+ diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5+ DLBCL and 60 patients with CD5− DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5− DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5+ DLBCL. Most patients with CD5+ DLBCL had lymph nodes with non–germinal center B-cell–like or activated B-cell–like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88 and CD79B mutations) in the CD5+ DLBCL cohort was higher than that in the CD5− DLBCL cohort (54.2% vs. 13.0%, P=0.005). Compared with the CD5− cohort, CD5+ DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P<0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5+ DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5+ DLBCL patients. In summary, CD5+ DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell–like and MCD subtypes with worse survival outcome.
Purpose The prognosis of patients with EBV- associated refractory/ relapsed Burkitt lymphoma (BL) is poor and there is no effective way to completely eliminate latent EBV infection. EBV was shown to transform from latency to lytic phase by histone deacetylase (HDAC) inhibitors, and EBV lytic activation could be inhibited by tenofovir, a potent inhibitor of EBV lytic DNA replication. Herein, we explored the anti-tumor effect and EBV clearance ability of novel HDAC inhibitor chidamide combined with tenofovir in EBV positive BL. Methods Raji, Namalwa and CA46 cells were used to evaluate the effects of chidamide combined with tenofovir on their cell viability, cell cycle and apoptosis induction. The EBV DNA copies and mRNA level of EBV related genes were detected by qPCR.Western blotting was performed to detect the cell cycle and apoptosis related pathways in BL cells. BL cell tumor-bearing NSG mice model was used to detect the anti-tumor effects of chidamide combined with tenofovir in vivo. Results In the study, chidamide exhibited HDAC inhibitory activity and downregulated the mRNA levels of HDAC1, 2, 3. Further, chidamide inhibited BL cell proliferation, arrested cell cycle progression, and induced BL cell apoptosis mainly through regulating MAPK pathway. Additionally, chidamide upregulated EBV DNA load and promoted the transcription of lytic genes including BZLF1, BMRF1, BMRF2 and BMLF1. Compared with chidamide alone, the addition of tenofovir further induced growth arrest and apoptosis, inhibited EBV lytic genes transcription and lytic DNA replication induced by chidamide in EBV positive BL cells. Furthermore, our in vivo data showed enhancive tumor-suppression effects of chidamide combined with tenofovir in BL cell tumor-bearing mice model. Conclusions The above data confirmed a synergistic effect of chidamide combined with tenofovir in inducing growth inhibition and apoptosis in EBV-positive BL cells.
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