Identification of an aberrant type of rearrangement in the T-cell receptor α/δ locus in adult T-cell leukemia

Abstract

V(D)J recombination is the mechanism by which antigen receptor genes are assembled by three basic steps: cleavage, processing of broken DNA ends, and joining. In this process of recombination, the broken DNA molecules excised from different receptor gene loci are often joined to generate interlocus joints. The interlocus recombination process contributes to the translocation between antigen receptor genes and oncogenes, leading to the malignant transformation of lymphocytes. The α and δ chain of the Tcell receptor (TCR α/δ) locus at chromosome 14q11 is also a region where several types of chromosome translocations occur in T-cell malignancies. In the process of analyzing TCR α rearrangements in a patient with adult T-cell leukemia (ATL) carrying a translocation at chromosome 14q11, we found novel complex rearrangements in the Jα locus. On the one hand, the V2.3 gene is joined to the heptamernonamer recombination signal sequence of the J37 gene, and, on the other hand, the J37 gene is joined to the V2.3 recombination signal sequence through head-to-head fusion. These recombination products or hybrid joints originated through an inversion of about 70 kb DNA. Interestingly, the inverted DNA stretch contains a normal V8.1-J40 rearrangement. These findings are the first direct demonstration that successive rearrangements with hybrid joints occur on the same chromosome in the human TCR α locus.

TCR variable gene involvement in chromosome inversion between 14q11 and 14q24 in adult T-cell leukemia

“…While Va involvement has been reported in very few cases, such as in secondary leukemia (Bernard et al 1988), ATL is often characterized by atypical rearrangements involving the Va gene. A complex rearrangement with inversion within the TCRa locus was previously found in ATL, where the rearrangement resulted as a consequence of hybrid joint formation, a type of faulty rearrangement between the RSS and the coding sequence (Saitou et al 2001). Sequence analysis in our patient showed the absence of conserved heptamer and nonamer signal sequences at the breakpoint junction, which implicated factors other than faulty recombination.…”

“…Moreover, since ATL cells are mature T-cell malignancies with a phenotype of CD3+, CD4+/ CD8À, the TCRa and b rearrangements have already been completed on both alleles at the time of leukemogenesis. Therefore, it is less likely that the faulty VJ joining of the TCRa locus during T-cell differentiation causes translocation in ATL (Saitou et al 2001). However, the Va region is still accessible for rearrangements in mature T-cells (Marolleau et al 1988), thus rendering it a major target for translocation in ATL.…”

HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase

“…Interestingly, NHEJ repair gene knockouts uniformly result exclusively in T-cell tumors (75)(76)(77), suggesting that the link among NHEJ, defective DSB repair, and clonal expansion may be particularly linear in the HTLV-1 host cell type. The isolation of V(D)J inversion events, a hallmark of DSB repair defects in lymphocytes, from patient-isolated ATL cells is strong evidence for the intimate role of NHEJ function and ATL development (78). Thus, resistance to damage repaired via the NHEJ pathway by HTLV-1 Tax may contribute to the endurance of HTLV-infected cells.…”