Molecular cloning of the breakpoint junction of a human chromosomal 8;14 translocation involving the T-cell receptor alpha-chain gene and sequences on the 3' side of MYC.

Abstract

The MOLT-16 cell line, which was established from the malignant cells of a patient with T-cell acute lymphoblastic leukemia, is characterized by a translocation involving chromosome 8 (band q24) and chromosome 14 (band qil) [t(8;14)(q24;qll)]. To determine the position of the gene encoding the a chain of the T-cell receptor and of the protooncogene MYC (formerly c-myc) in relation to the breakpoint junction and to evaluate their possible role in the pathogenesis of T-cell neoplasia, we applied the techniques of in situ chromosomal hybridization, Southern blot analysis, and molecular cloning to MOLT-16 cells. Our results indicate that the breakpoint on chromosome 14 at band qil occurs close to ajoining sequence of the gene encoding the a chain of the T-cell receptor. The constant region and part of the joining region of this gene are translocated to the 3' side of the MYC exons. The breakpoints on chromosomes 8 and 14 are close to, but distinct from, those found in SKW-3, another T-cell leukemia cell line, which has a t(8;14). The identification of a breakpoint to the 3' side of MYC suggests that this recurring translocation is analogous to the variant t(2;8) and t(8;22) translocations observed in the B-cell malignancies.

Sequence analysis of the MYC oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia T-cell line indicates that putative regulatory regions are not altered.

“…In a manner directly analogous to immunoglobulin/MYC juxtaposition in Burkitt lymphoma, translocation of Ca to the 3' MYC region results in MYC transcriptional activation specific to the 8q + chromosome (15), and the joining event mediating this deregulation has been reported at sites >36 kb upstream of the activated Ca locus (34,42). We have suggested (24) that the dominant effect on MYC transcription may be due to de novo association with an activated (immunoglobulin or TCR) locus.…”

Mechanisms of transcription factor deregulation in lymphoid cell transformation

“…The transcription factors affected by these molecular changes include genes encoding basic helix-loop-helix (bHLH) family members, such as TAL1 (Begley et al, 1989;Chen et al, 1990), TAL2 (Xia et al, 1991), LYL1 (Mellentin et al, 1989), MYC (Finger et al, 1986;McKeithan et al, 1986;Shima et al, 1986) and BHLHB1 (Wang et al, 2000); LIM-only domain (LMO) genes, such as LMO1 and LMO2 (McGuire et al, 1992); and the orphan homeobox genes HOX11 and HOX11L2 (Dube et al, 1991;Hatano et al, 1991;Kennedy et al, 1991;Lu et al, 1991;Dear et al, 1993;Bernard et al, 2001;Ferrando and Look, 2003), the major HOXA locus (Soulier et al, 2005) and MYB in young children (Clappier et al, 2007).…”

Molecular involvement of the pvt-1 locus in a gamma/delta T-cell leukemia bearing a variant t(8;14)(q24;q11) translocation.

“…These leukemic cells were clearly of the TCR -yb lineage, since the 8 gene on the other chromosome 14 was functionally rearranged and allowed cell surface expression of TCR -yb complex (32). Third, unlike all of the previous t(8;14)(q24;qll) rearrangements involving the TCR a locus and the c-myc locus (17,31,36,41), the Jb1 rearrangement to chromosome 8q24 in DOC leukemic cells appears to lie far from the structural locus of the c-myc oncogene.…”