TCL1 Oncogene Expression in B Cell Subsets from Lymphoid Hyperplasia and Distinct Classes of B Cell Lymphoma

Abstract

Activation of the TCL1 oncogene has been implicated in T cell leukemias/lymphomas and recently was associated with AIDS diffuse large B cell lymphomas (AIDS-DLBCL). Also, in nonmalignant lymphoid tissues, antibody staining has shown that mantle zone B cells expressed abundant Tcl1 protein, whereas germinal center (GC; centrocytes and centroblasts) B cells showed markedly reduced expression. Here, we analyze isolated B cell subsets from hyperplastic tonsil to determine a more precise pattern of Tcl1 expression with development. We also examine multiple B cell lines and B lymphoma patient samples to determine whether different tumor classes retain or alter the developmental pattern of expression. We show that TCL1 expression is not affected by Epstein-Barr virus (EBV) infection and is high in naïve B cells, reduced in GC B cells, and absent in memory B cells and plasma cells. Human herpesvirus-8 infected primary effusion lymphomas (PEL) and multiple myelomas are uniformly TCL1 negative, whereas all other transformed B cell lines tested express moderate to abundant TCL1. This observation supports the hypothesis that PEL, like myeloma, usually arise from post-GC stages of B cell development. Tcl1 protein is also detected in most naïve/GC-derived B lymphoma patient samples (23 of 27 [85%] positive), whereas most post-GC-derived B lymphomas lack expression (10 of 41 [24%] positive). These data indicate that the pattern of Tcl1 expression is distinct between naïve/GC and post-GC-derived B lymphomas (P < 0.001) and that the developmental pattern of expression is largely retained. However, post-GC-derived AIDS-DLBCL express TCL1 at a frequency equivalent to naïve/GC-derived B lymphomas in immune-competent individuals (7 of 9 [78%] positive), suggesting that TCL1 down-regulation is adversely affected by severe immune system dysfunction. These findings demonstrate that TCL1 expression in B cell lymphoma usually reflects the stage of B cell development from which they derive, except in AIDS-related lymphomas.

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

“…The transformation of pre-B cells of Em-myc transgenic mice is enhanced by v-Ha-ras and v-raf (Alexander et al, 1989). The BLs, on the other hand, are characterized by deregulated c-myc mainly owing to the 8:14 translocation, which juxtaposes c-myc to Ig heavy chain locus and high TCL1 expression (Said et al, 2001;Kiss et al, 2003). TCL1 transgenic mice develop Burkitt-like lymphoma with high penetrance (Bichi et al, 2002;Hoyer et al, 2002).…”

“…TCL1 transgenic mice develop B-cell malignancies such as Burkitt-like lymphoma, diffuse large B-cell lymphomas (DLBCLs), B-cell leukemias and follicular lymphomas (Bichi et al, 2002;Hoyer et al, 2002). TCL1 is also expressed in human B-and T-cell-derived tumors (Said et al, 2001;Kiss et al, 2003). The capacity of TCL1 to promote cell survival and growth has been attributed to its AKT-activating properties (Pekarsky et al, 2000).…”

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

“…32 The authors postulated that the deleterious effects of HIV on the host immune system could be responsible for the different clinical outcomes in AIDS vs non-AIDS patients with lymphoma. 20,32,33 In the context of B-lymphocyte development, an early immunohistochemical study of AIDS-related lymphomas proposed three phenotypic patterns corresponding to centroblasts, late germinal center/early postgerminal center B cells, and postgerminal center Bcells. 34 Another study, which included cases of both AIDS-related diffuse large B-cell lymphoma and Burkitt lymphoma, has suggested that there may be a shift away from the more chemoresistant lymphomas of postgerminal center origin because of the better immune function conferred by highly active antiretroviral therapy.…”

Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas

“…Dysregulated expression of TCL1 is a frequent molecular alteration in non-Hodgkin lymphomas (NHLs) that arise by transformation of germinal center (GC) B-cells (Teitell et al, 1999;Narducci et al, 2000;Said et al, 2001). Supporting an etiologic role in transformation, dysregulated expression of TCL1 in transgenic mouse B-cells throughout all stages of B-cell development promotes a spectrum of GC B-cell lymphoma subtypes that metastasize (Hoyer et al, 2002;Shen et al, 2006) or aggressive marginal zone-derived B-cell chronic lymphocytic leukemia (Bichi et al, 2002;Klein and Dalla-Favera, 2005;Yan et al, 2006).…”