DysregulatedTCL1promotes multiple classes of mature B cell lymphoma

Abstract

The TCL1 protooncogene is overexpressed in many mature B cell lymphomas, especially from AIDS patients. To determine whether aberrant expression promotes B cell transformation, we generated a murine model in which a TCL1 transgene was overexpressed at similar levels in both B and T cells. Strikingly, transgenic mice developed Burkitt-like lymphoma (BLL) and diffuse large B cell lymphoma (DLBCL) with attendant Bcl-6 expression and mutated J H gene segments at a very high penetrance beginning at 4 months of age. In contrast, only one mouse developed a T cell malignancy at 15 months, consistent with a longer latency for transformation of T cells by TCL1. Activation of premalignant splenic B cells by means of B cell antigen receptor (BCR) engagement resulted in significantly increased proliferation and augmented AKT-dependent signaling, including increased S6 ribosomal protein phosphorylation. Transgenic spleen cells also survived longer than wild-type spleen cells in long-term culture. Together these data demonstrate that TCL1 is a powerful oncogene that, when overexpressed in both B and T cells, predominantly yields mature B cell lymphomas.T he TCL1 (T cell leukemia 1) protooncogene is expressed in CD3 Ϫ CD4 Ϫ CD8 Ϫ precursor T cells and is extinguished at the CD4 ϩ CD8 ϩ stage of thymocyte development (1). In B cells, TCL1 is first expressed in pro-B cells and remains high in naive mantle zone B cells of peripheral lymphoid tissues (1-4). Downregulation of TCL1 expression in follicle center centroblasts and centrocytes is followed by gene extinction in post-germinal center (GC) memory B cells and plasma cells (4, 5).Continued high-level TCL1 expression, because of chromosomal rearrangements, was implicated in mature peripheral T cell malignancies (6, 7). Polyclonal and oligoclonal T cell expansions preceded clonal outgrowth by many years, suggesting that additional lesions were required for transformation (8,9). Supporting this tumorigenic mechanism, transgenic mice expressing TCL1-familymember proteins exclusively in T cells developed polyclonal T cell expansions before the evolution of clonal malignancies at 15 to 20 months (10, 11). Overexpression of TCL1, or MTCP1 (mature T cell proliferation 1), in mouse T cells did not affect B cell development or produce B cell lymphomas. These findings indicate that aberrant expression of TCL1 or MTCP1 in T cells perturbs T cell homeostasis through cell autonomous pathways without inducing premalignant or malignant changes in bystander B cells.About 15% of AIDS patients develop aggressive B cell nonHodgkin lymphoma (AIDS-NHL) (12, 13). Most AIDS-NHL originate from GC or post-GC B cells, but the early events leading to AIDS-NHL remain poorly defined (13,14). Diffuse large B cell lymphoma (DLBCL) is the most prevalent type of AIDS-NHL, and these tumors generally lack consistent genetic and͞or viral tumorpromoting alterations. Recently, abundant TCL1 expression was shown in a high percentage of AIDS-NHL of post-GC origin (3,4). This discovery led us to postulate that TCL1 dy...

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

“…NotI-EcoRV-HinfI RLGS profiles were generated on GC B-cell tumors, bulk non-neoplastic splenic tissue and sorted non-malignant splenic B or T cells from TCL1-tg mice (Hoyer et al, 2002) (Supplementary Figure 1). The use of methylation-sensitive NotI permitted the assessment of CpG methylation at the NotI landmark site.…”

“…Adoptive transfer of TCL1-tg LBL1 tumor cells into syngeneic mice results in the development of a phenotypically identical splenic lymphomas within 6 weeks (Hoyer et al, 2002). When the RLGS profiles of two of these daughter tumors (LBL1a and LBL1b) were compared with their LBL1 parental tumor, 1735 of the 1741 RLGS loci (99.6%) were identical (Table 1 and data not shown), indicating tumor-specific DNA methylation was stable for over 2 months (three weeks in culture and 6 weeks in syngeneic animals).…”

“…The TCL1-tg mouse model has been described (Hoyer et al, 2002) and is covered in greater detail in Supplementary methods. Human tissue and tumors were obtained from the UCLA Tissue Procurement Core Laboratory in accordance with institutional guidelines and Institutional Review Board (IRB) approval.…”

“…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). As TCL1 transgenic (TCL1-tg) mice develop lymphomas only after a prolonged latency (Hoyer et al, 2002) and fail to develop lymphomas for up to 20 months when crossed into a GC-deficient background (Shen et al, 2006), additional molecular alterations within the GC appear to be essential for B-cell transformation.…”

“…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). As TCL1 transgenic (TCL1-tg) mice develop lymphomas only after a prolonged latency (Hoyer et al, 2002) and fail to develop lymphomas for up to 20 months when crossed into a GC-deficient background (Shen et al, 2006), additional molecular alterations within the GC appear to be essential for B-cell transformation. Chromosomal translocations and aneuploidy have been identified in transformed GC B-cells in TCL1 transgenic mice (Shen et al, 2006), although it is unclear whether these genetic alterations drive or are merely reflective of the transformation process.…”