The role of TCL1 in human T-cell leukemia.
The TCL1 locus on human chromosome 14q32.1 is activated in T-cell leukemias by translocations and inversions that juxtapose it to regulatory elements of T-cell receptor genes. We isolated and characterized four genes at this locus, TCL1 and TCL1b (T-cell leukemia/lymphoma 1 and 1b), and TNG1 and TNG2 (TCL neighboring genes 1 and 2) all of which are overexpressed following rearrangements involving 14q32.1. TCL1 and TCL1b show 60% similarity and are represented in the mouse by a cluster of six homologous genes. In humans TCL1 and TCL1b show similar expression patterns: They are expressed mainly in CD4-/CD8- immature T-cells, pre B-cells and virgin B-cells. Expression decreases significantly at more mature stages of B-cell development. Activation of TCL1 and/or TCL1b in mature T-cells causes T-cell leukemia in humans. The oncogenic nature of TCL1 was confirmed by the analysis of a transgenic mouse model. Functional analysis of Tcl1 revealed its involvement in a PI3-kinase dependent Akt (PKB) pro-survival pathway through its interaction with the Akt kinase which increases Akt's enzymatic activity and promotes translocation of Akt to the nucleus.
Pekarsky
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Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street Philadelphia, Pennsylvania, PA 19107, USA. Carlo.Croce@mail.tju.edu
Hallas
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Croce
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D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015152:Blotting, Northern; D002883:Chromosomes, Human, Pair 14; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D011518:Proto-Oncogene Proteins; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C490393:Tcl1 protein, mouse; D014157:Transcription Factors