The murine Tcl1 oncogene: embryonic and lymphoid cell expression

Narducci, Maria Grazia; Virgilio, Laura; Engiles, Julie B.; Buchberg, Arthur M.; Billips, Linda G.; Facchiano, Antonio; Croce, Carlo M.; Russo, Giandomenico; Rothstein, Jay L.

doi:10.1038/sj.onc.1201246

Cited by 34 publications

(29 citation statements)

References 16 publications

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“…This could reflect the relatively low levels at which Tcl1 is expressed in mouse lymphocytes relative to human lymphocytes. 34,41 We also considered the possibility that the relatively modest phenotype seen in the Tcl1 Ϫ/Ϫ -deficient mice might represent a functional compensation by Tcl1 gene relatives. Tcl1 Ϫ/Ϫ mice and Tcl ϩ/ϩ /Tcl ϩ/Ϫ control mice immunized intravenously with SRBCs were bled at day 7 and day 15, and the serum samples analyzed for SRBC-specific IgM and IgG subclasses by ELISA (relative units/mL).…”

Section: Discussionmentioning

confidence: 99%

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

Kang

Narducci

Lazzeri

et al. 2005

Blood

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IntroductionT-cell prolymphocytic leukemias (T-PLLs) in humans often have chromosomal translocations that juxtapose the T-cell receptor (TCR) ␣/␦ or ␤ locus to the proximity of the T-cell leukemia/ lymphoma-1 gene (TCL1) located in the 14q32.1 region or, less frequently, to lay near its mature T-cell proliferation 1 (MTCP1) gene homolog in the Xq23 region. [1][2][3][4] The ensuing aberrant influence of a TCR enhancer element results in overexpression of the TCL1 or MTCP1 genes. 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. 13 An important clue to the role of TCL1 in the leukomogenesis process is provided by the functional linkage of Tcl1 to Akt kinase, an intracellular component that participates in the transduction of antiapoptotic and proliferative signals. 14,15 In the Akt signaling cascade, Tcl1 acts as an Akt cofactor to enhance kinase activity and nuclear translocation. 16,17 Tcl1 binding to Akt also facilitates the formation of Akt-Tcl1 hetero-oligomers. 18 The resultant (trans)phosphorylation of Akt1 at Ser473 may thus amplify the phosphatidylinositol 3 (PI3)-Akt1 pathway to contribute a survival advantage. 19 Normally, TCL1 expression is tightly regulated, being confined to lymphoid and germinal cells in humans and mice. In human B-lineage cells, TCL1 expression is initiated in pro-B cells, peaks in the pre-B cells, and persists in immunoglobulin M (IgM)-bearing B cells. 5 High expression levels of TCL1 transcripts have been found in the mantle zone B cells in the spleen, whereas TCL1 expression is down-regulated in germinal center and marginal zone B cells, and is extinguished in terminally differentiated plasma cells. [9][10][11] In human T-lineage cells, TCL1 expression is seen in the intrathymic CD4 Ϫ CD8 Ϫ subpopulation, but not in mature T cells. In the present study, we observed a similar pattern for Tcl1 expression in mouse T-and B-lineage cells. In order to gain insight into the physiologic role(s) that Tcl1 may have in T and B lymphopoiesis, we have examined both pathways of lymphocyte development and their cooperative function in antibody responses of Tcl1-deficient mice. These mice are shown to have modestly compromised T and B lymphopoiesis due either to impaired cellular proliferation or enhanced apoptosis. Materials and methodsMice, cell preparation, cell counting, and statistical analysis Tcl1 Ϫ/Ϫ and Tcl1 ϩ/Ϫ mice were generated as described previously. 20 Bone marrow (BM) cells were obtained by flushing the cavities of both femoral and tibial ...

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Section: Discussionmentioning

confidence: 99%

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

Kang

Narducci

Lazzeri

et al. 2005

Blood

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“…The Tcl1 genomic DNA was cloned from a 129͞SVJ mouse genomic library, as described (13), and subcloned into pBluescript SK vector (Stratagene). A targeting vector was designed to replace a 5-kb BamHI-HincII fragment containing exons 2, 3, and 4 by phosphoglycerate kinase (PGK)-neo in the same transcriptional orientation as the Tcl1 gene.…”

Section: Methodsmentioning

confidence: 99%

“…The developmentally regulated Tcl1 gene is normally expressed in ovary, testis, preimplantation embryos, fetal thymus, and bone marrow (12,13). To gain insight into the biological role(s) of Tcl1, we have generated Tcl1 null mutant mice.…”

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TCL1 participates in early embryonic development and is overexpressed in human seminomas

Narducci

Fiorenza

Kang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Overexpression of the TCL1 oncogene has been shown to play a causative role in T cell leukemias of humans and mice. The characterization of Tcl1-deficient mice in these studies indicates an important developmental role for Tcl1 in early embryogenesis. In wild-type embryos, Tcl1 is abundant in the first three mitotic cycles, during which it shuttles between nuclei and the embryo cortical regions in a cell-cycle-dependent fashion. The absence of this protein in early embryogenesis results in reduced fertility of female mice. 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. Even though Tcl1 ؊/؊ females display normal oogenesis and rates of oocyte maturation͞ovulation 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. Beyond this crisis point, differentiative traits of zygotic genome activation and embryo compaction can take place normally. In contrast with this unanticipated role in early embryogenesis, we observed an overexpression of TCL1 in human seminomas. This finding suggests that TCL1 dysregulation could contribute to the development of this germinal cell cancer as well as lymphoid malignancies.

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“…In the mouse, the syntenic region of human chromosome 14q32 is the region of the murine chromosome 12 proximal to the Ig locus. The murine Tcl1 protein shows a 50% homology to the human Tcl1 (8) and is expressed in fetal hematopoietic organs and in immature T and B cells as well as in adult spleen and thymus (8). To identify other members of the murine Tcl1 family we also have investigated the murine Tcl1 locus for the presence of homologous genes.…”

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Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes

Hallas

Pekarsky

Itoyama

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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TCL1 and TCL1b genes on human chromosome 14q23.1 are activated in T cell leukemias by translocations and inversions at 14q32.1, juxtaposing them to regulatory elements of T cell receptor genes. In this report we present the cloning, mapping, and expression analysis of the human and murine TCL1͞Tcl1 locus. In addition to TCL1 and TCL1b, the human locus contains two additional genes, TCL1-neighboring genes (TNG) 1 and 2, encoding proteins of 141 and 110 aa, respectively. Both genes show no homology to any known genes, but their expression profiles are very similar to those of TCL1 and TCL1b. TNG1 and TNG2 also are activated in T cell leukemias with rearrangements at 14q32.1. To aid in the development of a mouse model we also have characterized the murine Tcl1 locus and found five genes homologous to human TCL1b. Tcl1b1-Tcl1b5 proteins range from 117 to 123 aa and are 65-80% similar, but they show only a 30 -40% similarity to human TCL1b. 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. These data suggest a similar or complementary function of these proteins in early embryogenesis.

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The murine Tcl1 oncogene: embryonic and lymphoid cell expression

Cited by 34 publications

References 16 publications

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

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

TCL1 participates in early embryonic development and is overexpressed in human seminomas

Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes

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