Alternative titles; symbols
HGNC Approved Gene Symbol: TCL1A
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38): 14:95,709,947-95,714,125 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.13 | Leukemia/lymphoma, T-cell | 186960 | 2 |
Overexpression of the TCL1 gene in humans has been implicated in the development of mature T cell leukemia, in which chromosomal rearrangements bring the TCL1 gene in close proximity to the T-cell antigen receptor (TCR)-alpha (see 186880) or TCR-beta (see 186930) regulatory elements (summary by Virgilio et al., 1998). In normal T cells TCL1 is expressed in CD4-/CD8- cells, but not in cells at later stages of differentiation. TCL1 functions as a coactivator of the cell survival kinase AKT (164730) (Laine et al., 2000).
Virgilio et al. (1993) took advantage of chromosome-walking techniques and of P1 phage to clone and characterize 450 kb of the germline TCL1 locus, starting from the breakpoints of 2 independent T-cell leukemias. They found that both inversions and translocations occur within a 300-kb region in T-cell leukemias. In an attempt to identify a candidate oncogene responsible for malignant transformation, a CpG island centromeric to the translocations was identified. Two probes near the CpG island detected sequences conserved among species. In further studies, Virgilio et al. (1994) identified a gene within the 14q32.1 region of approximately 350 kb involved in translocations or rearrangements in T-cell leukemias and lymphomas. The gene, encoding a 1.3-kb transcript, was expressed only in restricted subsets of cells within the lymphoid lineage and was expressed in high levels in leukemic cells carrying a t(14;14)(q11;q32) translocation or an inv(14)(q11;q32) inversion. The cognate cDNA sequence revealed an open reading frame of 342 nucleotides encoding a protein of 14 kD. The TCL1 gene sequence appeared to show no homology with other human genes and is preferentially expressed early in T- and B-lymphocyte differentiation.
Virgilio et al. (1994) identified the TCL1 gene on chromosome 14q32.1, a region involved in chromosomal translocations and inversions in T cell leukemias and lymphomas.
In yeast 2-hybrid screening, Laine et al. (2000) found that TCL1 interacts with AKT (164730). All TCL1 isoforms bound to the AKT pleckstrin homology domain. Both in vitro and in vivo, TCL1 increased AKT kinase activity and as a consequence enhanced substrate phosphorylation. In vivo, TCL1 stabilized the mitochondrial transmembrane potential and enhanced cell proliferation and survival. The authors found that TCL1 forms trimers, which associate with AKT, in vivo. TCL1 was also found to facilitate the oligomerization and activation of AKT. The data showed that TCL1 is a novel AKT kinase coactivator that promotes AKT-induced cell survival and proliferation.
Narducci et al. (2002) observed an overexpression of TCL1 in human seminomas (273300), which suggested that TCL1 dysregulation could contribute to the development of this germinal cell cancer as well as lymphoid malignancies.
Kuraishy et al. (2007) noted that the germinal center (GC) is home to T-cell-independent antigen-driven B-cell maturation and memory B-cell and plasma cell production, and that it is the site of origin for most B-cell lymphomas. TCL1 expression is highest in immature B cells and lymphomas and low or absent in mature B cells and plasma cells. By sequence and chromatin immunoprecipitation analyses, Kuraishy et al. (2007) identified a CREB (123810) response element-like half-site in the TCL1 promoter, and they found that CREB expression supported robust basal activity of the TCL1 promoter. Activation of TCL1 was independent of phosphorylation of ser133 of CREB and was dependent on expression of TORC2 (608972) and phosphorylation of ser171 of TORC2. Knockdown of TORC2 resulted in marked repression of TCL1 expression in GC B cells, and confocal microscopy showed that nuclear localization of TORC2 was required for TCL1 expression. Kuraishy et al. (2007) proposed that a CREB/TORC2 regulatory mode controls the normal program of GC gene activation and repression that promotes B-cell development and circumvents oncogenic progression.
To show that transcriptional alteration of TCL1 is causally involved in the generation of T-cell neoplasia, Virgilio et al. (1998) generated transgenic mice that carried a TCL1 gene under the transcriptional control of the p56(lck) (153390) promoter element. Their results indicated that transcriptional activation of the TCL1 protooncogene can cause malignant transformation of T lymphocytes.
As indicated, the TCL1 gene 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 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 been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Bichi et al. (2002) described the phenotype of transgenic mice established with TCL1 under the control of the promoter enhancer of the immunoglobulin mu heavy chain (147020) to target TCL1 expression to immature and mature B cells. Flow cytometric analysis demonstrated a markedly expanded CD5(+) population in the peritoneal cavity of the mu-enhancer-TCL1 mice starting at 2 months of age and becoming evident in the spleen by 3 to 5 months and in the bone marrow by 5 to 8 months. Analysis of immunoglobulin gene rearrangements indicated 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 CLL (151400). The findings provided an animal model for CLL, the most common human leukemia, and demonstrated that deregulation of the TCL1 pathway plays a crucial role in CLL pathogenesis.
Overexpression of the TCL1 oncogene plays a causative role in T cell leukemias in humans and mice. The important developmental role of Tcl1 in early embryogenesis is characterized in Tcl1-deficient mice. In wildtype embryos, Tcl1 is abundant in the first 3 mitotic cycles, during which it shuttles between the nuclei and the embryo cortical regions in a cell-cycle-dependent fashion. Absence of this protein in early embryogenesis results in reduced fertility of female mice. Narducci et al. (2002) elucidated the mechanism responsible for the reduced female fertility through analysis of the oogenesis stages and early embryo development in Tcl1-deficient mice. Even though Tcl1 -/- females displayed normal oogenesis and rates of oocyte maturation/ovulation and fertilization, the lack of maternally derived Tcl1 impaired the embryo's ability to undergo normal cleavage and develop to the morula stage, especially under in vitro culture conditions. Beyond this crisis point, differentiative traits of zygotic genome activation and embryo compaction can take place normally.
The TCL1 protooncogene is overexpressed in many mature B-cell lymphomas, especially from AIDS patients. To determine whether aberrant expression promotes B cell transformation, Hoyer et al. (2002) generated a mouse model in which a TCL1 transgene was overexpressed at similar levels in both B and T cells. Strikingly, transgenic mice developed Burkitt-like lymphoma (see 113970) and diffuse large B-cell lymphoma with attendant expression of Bcl6 (109565) and mutated J(H) immunoglobulin gene segments at a very high penetrance beginning at 4 months of age. In contrast, only 1 mouse developed a T-cell malignancy at 15 months of age, consistent with a longer latency for transformation of T cells by TCL1. The data demonstrated that TCL1 is a powerful oncogene that, when overexpressed in both B and T cells, predominantly yields mature B-cell lymphomas.
An inversion of chromosome 14 due to breaks in q11.2 and q32.3 was found in a newly established childhood T-cell lymphoma cell line and confirmed in T-cell chronic lymphocytic leukemia by Hecht et al. (1984). In another T-cell lymphoma cell line, a t(10;14) translocation with a breakpoint at 14q11.2 was found. The authors proposed that a region in or near 14q11.2 is related to T-cell function. It may be significant that purine nucleotide phosphorylase (164050) and the alpha subunit of the T-cell antigen receptor (see 186880) map in this region. An alternative interpretation (Croce et al., 1985) is that an oncogene, TCL1, is situated at 14q32.3 and is activated when it comes into juxtaposition with the TCRA locus with inversion; see 186880 and 607585. Erikson et al. (1985) showed that the TCRA locus is split between the proximal V gene and the more distal C gene by the breakpoint at 14q11.2 that creates the t(11;14) of T-cell leukemia. Mathieu-Mahul et al. (1985) cloned a DNA fragment from 14q11 in a case of T-cell malignancy. Mengle-Gaw et al. (1988) and Davey et al. (1988) both studied chromosome rearrangements, inversions, or translocations, involving 14q in patients with ataxia-telangiectasia (208900). These patients are prone to the development of lymphatic neoplasms in association with these abnormalities. Mengle-Gaw et al. (1988) concluded that a single locus at chromosome band 14q32.1, located about 15-20 million basepairs centromeric to the IGH locus, is critical to the development of neoplasia. Davey et al. (1988) reached a similar conclusion, i.e., that a 'growth-effecting' gene in the 14q32 region participates in the leukemogenic process. Presumably this is the locus that has been referred to as TCL1.
Bichi, R., Shinton, S. A., Martin, E. S., Koval, A., Calin, G. A., Cesari, R., Russo, G., Hardy, R. R., Croce, C. M. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc. Nat. Acad. Sci. 99: 6955-6960, 2002. [PubMed: 12011454] [Full Text: https://doi.org/10.1073/pnas.102181599]
Croce, C. M., Isobe, M., Palumbo, A., Puck, J., Ming, J., Tweardy, D., Erikson, J., Davis, M., Rovera, G. Gene for alpha-chain of human T-cell receptor: location on chromosome 14 region involved in T-cell neoplasms. Science 227: 1044-1047, 1985. [PubMed: 3919442] [Full Text: https://doi.org/10.1126/science.3919442]
Davey, M. P., Bertness, V., Nakahara, K., Johnson, J. P., McBride, O. W., Waldmann, T. A., Kirsch, I. R. Juxtaposition of the T-cell receptor alpha-chain locus (14q11) and a region (14q32) of potential importance in leukemogenesis by a 14;14 translocation in a patient with T-cell chronic lymphocytic leukemia and ataxia-telangiectasia. Proc. Nat. Acad. Sci. 85: 9287-9291, 1988. [PubMed: 3194425] [Full Text: https://doi.org/10.1073/pnas.85.23.9287]
Erikson, J., Williams, D. L., Finan, J., Nowell, P. C., Croce, C. M. Locus of the alpha-chain of the T-cell receptor is split by chromosome translocation in T-cell leukemias. Science 229: 784-786, 1985. [PubMed: 3875152] [Full Text: https://doi.org/10.1126/science.3875152]
Hecht, F., Morgan, R., Hecht, B. K.-M., Smith, S. D. Common region on chromosome 14 in T-cell leukemia and lymphoma. Science 226: 1445-1447, 1984. [PubMed: 6438800] [Full Text: https://doi.org/10.1126/science.6438800]
Hoyer, K. K., French, S. W., Turner, D. E., Nguyen, M. T. N., Renard, M., Malone, C. S., Knoetig, S., Qi, C.-F., Su, T. T., Cheroutre, H., Wall, R., Rawlings, D. J., Morse, H. C., III, Teitell, M. A. Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma. Proc. Nat. Acad. Sci. 99: 14392-14397, 2002. [PubMed: 12381789] [Full Text: https://doi.org/10.1073/pnas.212410199]
Kuraishy, A. I., French, S. W., Sherman, M., Herling, M., Jones, D., Wall, R., Teitell, M. A. TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation. Proc. Nat. Acad. Sci. 104: 10175-10180, 2007. [PubMed: 17548807] [Full Text: https://doi.org/10.1073/pnas.0704170104]
Laine, J., Kunstle, G., Obata, T., Sha, M., Noguchi, M. The protooncogene TCL1 is an Akt kinase coactivator. Molec. Cell 6: 395-407, 2000. [PubMed: 10983986] [Full Text: https://doi.org/10.1016/s1097-2765(00)00039-3]
Mathieu-Mahul, D., Caubet, J. F., Bernheim, A., Mauchauffe, M., Palmer, E., Berger, R., Larsen, C.-J. Molecular cloning of a DNA fragment from human chromosome 14(14q11) involved in T-cell malignancies. EMBO J. 4: 3427-3433, 1985. [PubMed: 3912169] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb04100.x]
Mengle-Gaw, L., Albertson, D. G., Sherrington, P. D., Rabbitts, T. H. Analysis of a T-cell tumor-specific breakpoint cluster at human chromosome 14q32. Proc. Nat. Acad. Sci. 85: 9171-9175, 1988. [PubMed: 3194418] [Full Text: https://doi.org/10.1073/pnas.85.23.9171]
Narducci, M. G., Fiorenza, M. T., Kang, S.-M., Bevilacqua, A., Di Giacomo, M., Remotti, D., Picchio, M. C., Fidanza, V., Cooper, M. D., Croce, C. M., Mangia, F., Russo, G. TCL1 participates in early embryonic development and is overexpressed in human seminomas. Proc. Nat. Acad. Sci. 99: 11712-11717, 2002. [PubMed: 12181493] [Full Text: https://doi.org/10.1073/pnas.182412399]
Virgilio, L., Isobe, M., Narducci, M. G., Carotenuto, P., Camerini, B., Kurosawa, N., ar-Rushdi, A., Croce, C. M., Russo, G. Chromosome walking on the TCL1 locus involved in T-cell neoplasia. Proc. Nat. Acad. Sci. 90: 9275-9279, 1993. [PubMed: 8415691] [Full Text: https://doi.org/10.1073/pnas.90.20.9275]
Virgilio, L., Lazzeri, C., Bichi, R., Nibu, K., Narducci, M. G., Russo, G., Rothstein, J. L., Croce, C. M. Deregulated expression of TCL1 causes T cell leukemia in mice. Proc. Nat. Acad. Sci. 95: 3885-3889, 1998. [PubMed: 9520462] [Full Text: https://doi.org/10.1073/pnas.95.7.3885]
Virgilio, L., Narducci, M. G., Isobe, M., Billips, L. G., Cooper, M. D., Croce, C. M., Russo, G. Identification of the TCL1 gene involved in T-cell malignancies. Proc. Nat. Acad. Sci. 91: 12530-12534, 1994. [PubMed: 7809072] [Full Text: https://doi.org/10.1073/pnas.91.26.12530]