The cell of origin of Burkitt lymphoma: germinal centre or not germinal centre?

Abstract

of Park D. and Colleagues that reports novel insight into the early histopathogenesis of immunodeficiency-associated Burkitt lymphoma (BL) suggesting a possible relationship with monocytoid B-cell and wondering the cell of origin of BL. In addition, the manuscript raises the question of the polymicrobial nature of BL as cytomegalovirus (CMV) was also detected. Accepted ArticleThis article is protected by copyright. All rights reserved.We wish to point out, however, that previous published papers demonstrated that all BL subtypes are definitely related to germinal center (GC) B-lymphocytes (1). Interestingly, follicular colonization or follicular growth can be occasionally observed in BL samples ( Figure 1) (2). On the other hand, it has been hypothesized that endemic and human immunodeficiency virus (HIV)-related BL cases, which are commonly associated with Epstein-Barr virus (EBV) infection, may derive from a later developmental stage of B-cells than sporadic BL, i.e. post-germinal center/memory B-cells (3). This is in line with the fact that in healthy carriers, EBV resides in memory IgM-positive B-cells that re-enter the GC reaction following antigen stimulation (4). In fact, activation of B-cell receptor by malaria infection and/or other pathogens induces the clonal expansion of memory B-cells, that express EBNA-1 (latency I) and activation induced cytidine deaminase (AID) when they divide (5). EBNA-1 expression in this subset of cells allows viral DNA to replicate and may thus result in the upregulation of hsa-miR-127 and in the shift to the characteristic GC phenotype and re-entry into the GC reaction (6). The finding of clusters of BL cells intermingled with monocytoid B-cells may thus well represent the first in vivo picture of the origin of BL from this IgM-positive memory B-cells subset, during clonal expansion under the pressure of antigens (Figure 2). The MYC/IgH translocations may thus occur during clonal expansion of activated memory B-cells or when they reenter the GC, being the active form of AID expressed regardless of the stage of B-cell (7). Park et al. point at a direct role of CMV in promoting BL by directly infecting B-cells. However, no evidences of such phenomenon are present in the literature so far, and the data presented by the authors are insufficient to draw this conclusion. In fact, CMV was identified only in the original specimen but not in the subsequent BL. Therefore, it is unlikely that the virus had been integrated into B-cells. In addition, a recent study on endemic BL (eBL) detected the presence of CMV only in bystander cells, raising the possibility that CMV infection along with other microbes may contribute to the chronic antigenic stimulation in which eBL occurs and may also induce EBV lytic cycle through B-cell reactivation and spreading of EBV infection out of its natural niche of memory B-cells (8).

Clinicopathological features and EBV infection status of lymphoma in children and adolescents in South China: a retrospective study of 662 cases

“…EBV can be detected in more than 95% of endemic BL cases and approximately 20-30% of sporadic BL by EBERs. Molecular profiles and significant pathways of endemic BL and sporadic BL are different [ 33 ]. Endemic and HIV-related BL cases may derive from a later developmental stage of B cells, i.e.…”

Burkitt lymphoma with a granulomatous reaction: an M1/Th1‐polarised microenvironment is associated with controlled growth and spontaneous regression

“… 42 , 43 This is in line with the fact that, in healthy carriers, EBV resides in memory B cells that re‐enter the GC reaction following antigenic stimulation. 44 , 45 , 46 Only one case with similar features has been recently reported in the literature, in a human immunodeficiency virus (HIV)‐positive female, 47 and was reported as ‘Burkitt microlymphoma’. We have also observed a similar case in an HIV‐positive patient (Figure S5).…”

Primary bone diffuse large B‐cell lymphoma (PB‐DLBCL): a distinct extranodal lymphoma of germinal centre origin, with a common EZB‐like mutational profile and good prognosis

“…Correlations of HTS and FISH data showed characteristic profiles seen in other lymphomas. Mutations of CREBBP correlated with that in HIST1H1E and/or KMT2D, featuring GCB DLBCL, FL and Burkitt lymphoma 17,[32][33][34][35] ; ARID1A and CCND3 mutations 14,15 Since none of the PB-DLBCL patients presented stage III disease, stage III R-CHOP treated patients were omitted for appropriate comparison. The distribution of stage I and II diseases differed between the cohorts.…”