Human chronic lymphocytic leukemia modeled in mouse by targetedTCL1expression

Abstract

The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, E-TCL1, established with TCL1 under the control of a VH promoter-IgH-E enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5 ؉ population in the peritoneal cavity of E-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3-5 mo and in the bone marrow by 5-8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5 ؉ B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

“…With T regdepleting and T reg -increasing substances in hand, [28][29][30][31] we have the means to test this hypothesis in preclinical tumor models, such as the Tcl1-mouse model for CLL. 32,33 …”

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

“…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). Whether and how c-myc and TCL1 cooperate toward the development of BL is, however, not known.…”

“…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).…”

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). 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.…”