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SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation

ABSTRACT: Sirtuin-2 (SIRT2) is a cellular deacylase, regulating cell cycle progression and metabolic homeostasis. Recently, SIRT2 has emerged as a target with both anticancer and antiviral potential. However, the role and targetability of SIRT2 in viral-driven cancers remains unexplored. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with oncogenic potential that establishes latency in B lymphocytes and is typically controlled by a robust T cell immune response. In settings that compromise this response, such as immune suppression following transplant, EBV can cause B cell lymphomas. With broad immunosuppression and varying response rates limiting the effectiveness of existing lymphoma therapeutics, new strategies are necessary. SIRT2 modulation significantly alters gene expression and metabolism of EBV-infected B cells. Treatment with SIRT2 modulators drives hyperacetylation of targets involved in lipid metabolism, central carbon metabolism, and oxidative phosphorylation. EBV-positive and EBV-negative B cell lymphomas rely on glycolysis to avoid cell death after SIRT2 modulation, revealing a metabolic vulnerability that can be harnessed to kill lymphoma cells. Overall, we have identified how SIRT2 could be implicated as a novel target of therapeutic potential for B cell lymphomas, while also defining fundamental roles for extranuclear lysine acetylation in regulating B cell proliferation and metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342301 | GEO | 2026/08/06

REPOSITORIES: GEO

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Project description:Epstein–Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathologic entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histological and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma in 57 patients aged ≥50 years, including 35 EBV+ DLBCL (12 polymorphic DLBCL [pDLBCL] and 23 monomorphic DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon-γ (IFNγ)-enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8), but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; interquartile range [IQR], 42%–89%), but lower in pDLBCL (18%; IQR, 12%–23%) and mDLBCL (5%; IQR, 0%–30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFNγ-mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. EBV+ large B-cell lymphoma spectrum was reclassified into four molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1-alteration (n = 9, 20%); (3) high IFNγ signature score (n = 9, 20%), and (4) low IFNγ signature score (n = 18, 39%). Moreover, these groups were identified using surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing tumor–host interaction enhances understanding of the EBV+ large B-cell lymphoma spectrum and benefits pathological diagnosis and clinical management.

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SIRT2 deacylase modulators control B cell metabolic reprogramming in EBV infection and mitogenic activation

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