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...

AIDS-related non-Hodgkin's lymphoma (AIDS NHL) comprises a diverse and heterogeneous group of high-grade B cell tumors. Certain classes of AIDS NHL are associated with alterations in oncogenes or tumor-suppressor genes or infections by oncogenic herpesviruses. However, the clinically significant class of AIDS NHL designated immunoblastic lymphoma plasmacytoid (AIDS IBLP) lacks any consistent genetic alterations. We identified the TCL1 oncogene from a set of AIDS IBLP-associated cDNA fragments generated by subtractive hybridization with non-AIDS IBLP. Aberrant TCL1 expression has been implicated in T cell leukemia/lymphoma development, and its expression also has been seen in many established B cell tumor lines. However, TCL1 expression has not been reported in AIDS NHL. We find that TCL1 is expressed in the majority of AIDS IBLP tumors examined. AIDS-related non-Hodgkin's lymphoma (AIDS NHL) occurs in up to 10% of HIV-infected individuals who have moderate to severe immunodeficiency (1-3). These lymphomas are biologically and genetically heterogeneous, are derived from germinal center or postgerminal center B cells, and are classified according to body location and histologic criteria (reviewed in refs. 4-7). Certain AIDS NHL classes are associated with specific oncogenic lesions or viral involvement. For example, AIDS-related Burkitt's lymphoma usually contain activating c-MYC translocations, whereas AIDS-related primary-effusion lymphoma consistently contain human herpesvirus-8 (8-24). AIDS diffuse large B cell lymphoma accounts for 70% of systemic lymphomas and is the second most common type of cancer after Kaposi's sarcoma in AIDS patients (25,26). Systemic AIDS diffuse large B cell lymphoma are further classified into two subclasses (6,7,(27)(28)(29). AIDS large noncleaved-cell lymphoma is postulated to originate from germinal center B cells and often exhibits dysregulated expression of the BCL-6 protooncogene because of chromosomal translocations or promoter mutations. AIDS immunoblastic lymphoma plasmacytoid (AIDS IBLP) is thought to derive from postgerminal center B cells and is not associated with any predominant genetic alteration (30, 31). AIDS IBLP are monoclonal tumors that usually contain Epstein-Barr virus, indicating that they are not simply Epstein-Barr virusdriven polyclonal proliferations. The lack of any consistently associated oncogene involvement in AIDS IBLP strongly suggests that these tumors arise through novel patterns of dysregulated gene expression (7,15,32).We sought to identify differentially expressed genes in AIDS IBLP patient samples versus non-AIDS lymphoma samples by using suppression subtractive hybridizations (SSH) (33,34). Large cell lymphomas with immunoblastic/plasmacytoid features consistent with postgerminal center derivations (IBLP) were selected for these subtractions from HIV-infected or uninfected patient samples. The TCL1 oncogene was identified among multiple differentially expressed genes isolated from AIDS IBLP in these studies.TCL1 is developmentally reg...