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

Abstract

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 ...

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

“…Tcl1 À/À mice develop alopecia and skin impairment: macroscopical and histopathological analysis Tcl1 À/À mice show no gross histological or physical abnormality at birth, except a fertility defect and a mild impairment of the immune system in adult life (Kang et al, 2005;Narducci et al, 1997aNarducci et al, , b, 2002. These mice develop a form of mild alopecia starting from the head and neck region (Figure 1, Supplementary Figures S1 and S2).…”

“…Here we show that CD34 þ cells are diminished in Tcl1 À/À mice. We do not know if and how Tcl1 regulates CD34 expression; however, it has already been reported that Tcl1 and CD34 are co-expressed in the lymphoid compartment in the very early stage of B-cell differentiation (pro-B cells) (Narducci et al, 2000), and that this compartment of pro-B cells is also less numerous in the Tcl1 À/À mice (Kang et al, 2005).…”

“…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). Functionally, Tcl1 exerts its function by binding the pleckstrin domain of AKT proteins, thereafter increasing AKT kinase activity and enhancing AKT nuclear translocation in vitro (Laine et al, 2000;Pekarsky et al, 2000;Kunstle et al, 2002) and in vivo (Zanesi et al, 2006).…”

“…Since we made Tcl1 À/À mice more than 5 years ago, we have observed that the Tcl1 À/À mice, other than the lymphoid and embryonic non-lethal phenotypes (Narducci et al, 2002, Kang et al, 2005, show a skin defect in adults with the onset of alopecia followed by skin wounding. As the epidermis provides a model tissue to investigate proliferation and self-renewal mechanisms, particular attention has been focused on hair follicles (HFs) as they go through cyclic regeneration that comprises degenerative (catagen), resting (telogen) and regenerative (anagen) phases (Stenn and Paus, 2001).…”

Incorporation of Glycosylphosphatidylinositol-Anchored Granulocyte- MacrophageColony-Stimulating Factor or CD40 Ligand Enhances Immunogenicity of Chimeric Simian Immunodeficiency Virus-Like Particles

“…Bone marrow cells were prepared as described elsewhere (23). Bone marrow cells (1 ϫ 10 6 ) were labeled with CFSE (carboxyfluorescein diacetate, succinimidyl ester) (Molecular Probes, Eugene, OR) at a final concentration of 1 M, and CFSE was quenched by further incubation in serumcontaining medium and extensively washed in RPMI medium.…”