The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis.

Abstract

T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.

Telomere Position Effect and Silencing of Transgenes near Telomeres in the Mouse

“…In some respects, our findings are consistent with studies of human tumor cell lines, which also utilized telomeric transgenes to demonstrate the presence of a substantial TPE (4,31). However, we also found several significant differences between TPE in mice and that reported for human tumor cells.…”

“…However, it is important that the transgenes in clone A405 are integrated into the promoter of the hnRNP A1 gene (unpublished observation), which is actively expressed in proliferating cells (7) and therefore might influence the effect of TSA on TPE. Regardless, the increase in expression level of the transgenes after TSA treatment (2.2-and 1.5-fold for the neo and HSV tk genes, respectively) was still much less than the 10-to 50-fold increase in expression reported for the telomeric transgenes in a human tumor cell line (4). This difference in response between mouse ES cells and human tumor cells to TSA may be an indication of different mechanisms for generating TPE in these cells, although it may also reflect differences in metabolism or uptake of TSA.…”

The murine Tcl1 oncogene: embryonic and lymphoid cell expression

“…This gene is known to be involved in the pathogenesis of human mature T-cell proliferations, such as T-PLL and in similar leukemias originating with high frequency in patients with AT (Taylor, 1982;Baer et al, 1987;Croce et al, 1985;Heim and Mitelman, 1987;Russo et al, 1988;Bertness et al, 1990;Wei et al, 1990;Brunning, 1991;Croce, 1991). This gene is also overexpressed in Adult T-cell leukemias, a T-lymphoproliferation that shares many similarities to T-PLL and associated with endemic infection of the HTLV-I virus (Narducci et al, unpublished results).…”

“…Identification of the genes responsible has been possible due to the large number of chromosomal rearrangements that have been found in speci®c types of hematopoietic tumors Baer et al, 1987;Bertness et al, 1990;Cleary, 1991;Croce, 1991). These chromosomal rearrangements have provided cytogenetic landmarks for studies directed at identifying and cloning the genes involved in cancer.…”

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.

“…To date, there is no evidence that a TCR gene is found at this position, and thus it has been speculated that the region may contain a cellular transforming gene important in the etiology of T-cell malignancies (18,19 indicates that a site-specific recombination event has led to the joining of a joining (J) region gene (Ja) from within TCRA to a segment of DNA located at position 14q32 centromeric to the IGH locus. The 14q32 restriction map and sequence data** from the breakpoint region lacks homology with other breakpoints previously reported from this region (16,17,20).…”