Molecular Analysis of T-Cell Receptor Gene Rearrangements in Children with T-Cell Acute Lymphoblast Leukemia on DFCI ALL Consortium Protocol 95-01.

During normal T-cell differentiation, T-cell receptor (TCR) genes undergo recombination in an ordered way. TCRd genes rearrange first followed by TCRg genes, which may result in TCRgd+ T lymphocytes. TCRab T lymphocytes develop via a separate differentiation lineage, with TCRb preceding TCRa gene rearrangements. Unlike in normal T-cells, TCRd, TCRg and TCRb genes rearrangements can be detected in T-cell acute lymphoblastic leukemia (T-ALL) and these rearranged gene sequences can be used as molecular targets to detect minimal residual disease (MRD). Knowledge of the association between rearrangement patterns and disease pathogenesis of pediatric T-ALL is relatively limited. We analyzed 45 sequences of the TCR gene rearrangements (17 TCRd and 28 TCRg) obtained at presentation from 37 children with T-lineage ALL and these sequences were used as molecular targets to perform real-time PCR (RQ-PCR). Seven children had both TCRd and TCRg gene rearrangements. Sequence analysis revealed a higher frequency of Vd1-Jd1 rearrangements (88%) compared to Vd2-Jd1 (6%) and Vd2-Dd3 (6%). Of the 28 TCRg sequences, Vg2 gene segment was identified in 7 sequences, followed by Vg4 (5), Vg3 (4), Vg8 (4), Vg1 (2), Vg7 (2), Vg10 (2), Vg5 (1), and Vg9 (1). In keeping with previous findings the median number of nucleotides in the junctional regions was higher in TCRd (28bp) than in TCRg sequences (7.5bp, p 10−3. However, there was no difference in EFS in these three groups, and only one patient relapsed. We conclude that TCRg/d rearrangements provide suitable markers for RQ-PCR MRD analysis, but that in this treatment protocol high levels of MRD at the end of induction are not necessarily predictive of relapse in T-lineage ALL as they are in B-lineage ALL