Disease relevance of Tcl1

• Because the virus containing the v-akt oncogene causes T-cell lymphoma in mice and Akt is a key player in transduction of antiapoptotic and proliferative signals in T-cells, we investigated whether Akt and Tcl1 function in the same pathway [1].
• Members of the TCL1 family of oncogenes are abnormally expressed in mature T-cell leukemias and B-cell lymphomas [2].
• Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice [3].
• Aging transgenic mice that overexpress TCL1 under control of the mu immunoglobulin gene enhancer, develop a CD5+ B cell lymphoproliferative disorder mimicking human CLL and implicating TCL1 in the pathogenesis of CLL [3].
• In contrast with this unanticipated role in early embryogenesis, we observed an overexpression of TCL1 in human seminomas [4].

Psychiatry related information on Tcl1

• The lck-TCL1 transgenic mice developed mature T cell leukemias after a long latency period [5].

High impact information on Tcl1

• 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 [6].
• The present studies elucidate the mechanism responsible for the reduced female fertility through analysis of the oogenesis stages and early embryo development in Tcl1-deficient mice [4].
• Even though Tcl1(-/-) females display normal oogenesis and rates of oocyte maturation/ovulation and fertilization, the lack of maternally derived Tcl1 impairs the embryo's ability to undergo normal cleavage and develop to the morula stage, especially under in vitro culture conditions [4].
• Overexpression of the TCL1 oncogene has been shown to play a causative role in T cell leukemias of humans and mice [4].
• Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression [6].

Biological context of Tcl1

• Thus, we demonstrate that Tcl1 is a cofactor of Akt1 that enhances Akt1 kinase activity and promotes its nuclear transport [1].
• The marginal zone B cells and T-cell-independent antibody responses were also diminished in Tcl1(-/-) mice [7].
• In Tcl1-deficient mice, we found B lymphopoiesis to be compromised at the pre-B cell stage and T-cell lymphopoiesis to be impaired at the CD4(+)CD8(+) thymocyte stage [7].
• The locus order and distances of the three genes and microsatellite loci were estimated as follows: [centromere] - Tcl1-(> or =0.085 cM)-D12Mit50-(0.085 cM)D12Mit132-(1.96 cM)D12Mit122-(0.085 cM)D12Mit53-(1.37 cM)-[D12Mit233,D12Mit279,Yy1]-(0.085 cM)-D12Mit181-(> or =0.17 cM)-Tnfalphaip2 - [telomere] [8].
• Tcl1 proteins are approximately 15 kD and share 25-80% amino acid sequence identity [2].

Anatomical context of Tcl1

• Coimmunoprecipitation experiments showed that endogenous Akt1 and Tcl1 physically interact in the T-cell leukemia cell line SupT11; both proteins also interact when cotransfected into 293 cells [1].
• The intracellular localization of Tcl1 and Akt1 in mouse fibroblasts was investigated by immunofluorescence [1].
• Impaired T- and B-cell development in Tcl1-deficient mice [7].
• The sequences and crystal structures of three Tcl1 proteins were analyzed in order to understand their interactions with Akt/PKB and the implications for lymphocyte malignancies [2].
• All five mouse Tcl1b and murine Tcl1 mRNAs are abundant in mouse oocytes and two-cell embryos but rare in various adult tissues and lymphoid cell lines [9].

Associations of Tcl1 with chemical compounds

• In the present report, we have produced, using a bacterial expression system, the purified murine Tcl1 protein and a mutant form of murine Tcl1 protein containing a cysteine to alanine mutation at amino acid position 85 [10].
• The MTCP-1 recombinant proteins display greater solubility, do not form disulfide linked dimers or oligomers, and elute at a lower isopropanol concentration than the corresponding TCL-1 proteins [11].
• We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia [12].

Physical interactions of Tcl1

• Tcl1 interacts physically with Akt, increases its kinase activity and facilitates its transport to the nucleus [13].

Other interactions of Tcl1

• This approach allowed us to verify the involvement of the Tcl1/Akt/mTOR biochemical pathway in the disease by testing the ability of a specific pharmacologic agent, rapamycin, to slow CLL [3].
• These results suggest that Tcl1, Yy1 and Tnfalphaip2 genes are not predominantly involved in radiation lymphomagenesis of mice [8].
• Investigations of these mouse models revealed that deregulation of three pathways, Tcl1-Akt pathway, TNF-NF-kB pathway, and Bcl2-mediated anti-apoptotic pathway, result in the development of B-CLL [14].

Analytical, diagnostic and therapeutic context of Tcl1

• 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 [6].
• TCL1 expression was observed in both the cytoplasmic and nuclear compartments, as confirmed by Western blot analysis [15].
• The TCL1 expression and EBV status of 14 sporadic pediatric BL cases was determined by immunohistochemical staining for TCL1 and in situ hybridization for EBV-encoded RNA (EBER) [16].
• Dot-blot immunoassays and ELISA indicated that CSF-1 was secreted by TCL-1 cells, at levels comparable to primary trophoblast cells and BeWo choriocarcinoma (trophoblast tumour) cells [17].
• Reverse transcriptase-polymerase chain reaction analysis confirmed the presence in TCL-1 cells of CSF-1 receptor mRNA (c-fms gene product), indicating that the components of a potential autocrine loop were present in these cells [17].

References