Deregulated expression of TCL1 causes T cell leukemia in mice

Abstract

The TCL1 oncogene on human chromosome 14q32.1 is involved in the development of T cell leukemia in humans. 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. The TCL1 oncogene is activated in these leukemias by juxtaposition to the ␣ or ␤ locus of the T cell receptor, caused by chromosomal translocations t(14:14)(q11:q32), t(7:14)(q35:q32), or by inversions inv(14)(q11:q32). To show that transcriptional alteration of TCL1 is causally involved in the generation of T cell neoplasia we have generated transgenic mice that carry the TCL1 gene under the transcriptional control of the p56 lck promoter element. The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period. Younger mice presented preleukemic T cell expansions expressing TCL1, and leukemias developed only at an older age. The phenotype of the murine leukemias is CD4 ؊ CD8 ؉ , in contrast to human leukemias, which are predominantly CD4 ؉ CD8؊ . These studies demonstrate that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes, indicating the role of TCL1 in the initiation of malignant transformation in T prolymphocytic leukemias and T chronic lymphocytic leukemias.

Impaired T- and B-cell development in Tcl1-deficient mice

“…46 Transgenic mice that overexpress either Tcl1 or its MTCP1 homologue also have exaggerated T-and B-cell proliferation and they develop leukemias. 7,8,12,13 By contrast, Tcl1-deficient mice are shown in the present study to manifest precisely the opposite effects of those seen in Akt transgenic mice. It may therefore be of interest to cross these animal models in future studies to explore the coordinate roles of the Tcl1 and Akt genes in BCR/TCR-mediated signaling and clonal selection.…”

“…Since earlier studies suggest roles for the human TCL1 gene product in cellular proliferation 7,8 and in antiapoptotic signaling, 10,16,17 we tested the effects of apoptotic and proliferative stimuli under in vivo and in vitro conditions. When the rate of spontaneous apoptosis was assessed by measuring cell viability in thymocytes cultured in media or for thymocytes stimulated with dexamethasone, significant differences were not observed for the wild-type and null mice (data not shown).…”

“…5,6 Overexpression of either TCL1 or MTCP1 in transgenic mouse models employing a T-cell-specific promoter may also result in a T-cell leukemia that resembles human T-PLL. 7,8 In addition to the implicit TCL1 involvement in this T-cell malignancy, a variety of B-lineage tumor cell lines, ranging from pre-B cell to mature B-cell phenotype, have also been shown to express high Tcl1 levels. [9][10][11] Moreover, TCL1 overexpression under the control of B-lineage-specific enhancer and promoter elements has been shown to promote B-cell chronic lymphocytic leukemia 12 and B-cell lymphomas in mice.…”

Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32)

“…Transgenic mouse studies have demonstrated that overexpression of TCL1 induces T-cell malignancies in these animals suggesting that TCL1 plays a causal role in the transformation process. 10 More recently, TCL1 was shown to physically interact with the Akt survival kinase which is then activated and translocated to the nucleus, which may explain at least in part the oncogenic potential of TCL1 at the molecular level. 41 Reassuringly, we found that TCL1A, but not TCL1B and TNG2, was highly expressed in the T-PLL samples, whereas it could not be detected in ND-derived T cells and a T-PLL case lacking inv(14)/t(14;14) (Figure 2).…”

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

“…Thus, TCL1 contributes to T-PLL by increasing cell proliferation and/or cell survival. Three transgenic mouse models carrying TCL1 under the control of T-and B-cell promoters develop mature T-and B-cell leukemia, thus confirming the oncogenic role of TCL1 overexpression (Virgilio et al, 1998;Bichi et al, 2002;Hoyer et al, 2002). Moreover, TCL1 has been shown to be constitutively expressed in a tightly regulated manner in lymphoid cells of B and T origins (Narducci et al, 1997a, b;Takizawa et al, 1998;Teitell et al, 1999;Kang et al, 2005).…”