Characterization of the TCLI Gene and Its Involvement in T-Cell Malignancies

Abstract

Most human leukemias and lymphomas exhibit non-random chromosomal alterations. Translocations are the most common form of alteration in hematopoetic malignancies, leading to oncogenic activation either by the formation of chimeric transforming genes or by deregulation of transcription (Croce, 1987; Rabbitts, 1994). Gene fusion is observed in the majority of the myeloid tumors and in soft tissue sarcomas, and less frequently in B and T cell leukemias and lymphomas: good examples of these alterations are the t(9;22) translocation of chronic myelogenous leukemia (CML) and Ph chromosome positive acute lymphocytic leukemia (Ph+ALL) and the t(1;19), t(15;17), t(6;9) and t(4;11) chromosomal translocations observed in pre-B, myeloid and mixed lineage leukemias, all of which generate chimeric transcripts (Nourse et al., 1990, Kamps et al., 1990, and Gu et al. 1992). Deregulation of oncogene transcription is observed in most B and T cell leukemias and lymphomas, in these alterations the immunonoglobulin (Ig) or the T-cell-receptor (TCR) loci become juxtaposed to cellular protoncogenes such as c-MYC, BCL-2, TCL-2, BCL-1, TCL-3 (for a review see Croce, 1987; Rabbitts, 1994). In this latter case the gene justaxposed to the Ig or the TCR locus can be quite close (within 10–30 kb) from the genomic breakpoint, as for BCL-2 on chromosome 18q21, BCL-3 on chromosome 19q13.1, c-MYC on 8q24 in sporadic cases of Burkitt Lymphomas (BLs),or far (up to few hundreds kilobases) as for BCL-1 on chromosome 11q13, and c-MYC, in the endemic cases of BLs. These translocations are belived to be due to errors during the physiological process of the Ig and TCR gene rearrangements, and result in the activation of oncogenes by their juxtaposition to regulatory elements (enhancers) of the Ig or TCR loci.