Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL

Abstract

A total of 28 children and nine adults with relapsed T-ALL were analyzed for the configuration of their T-cell receptor (TCR) and TAL1 genes at diagnosis and relapse to evaluate their stability throughout the disease course. A total of 150 clonal TCR and TAL1 gene rearrangements were identified in the 37 patients at diagnosis. In 65% of cases all rearrangements and in 27% of cases most rearrangements found at diagnosis were preserved at relapse. Two children with unusually late T-ALL recurrences displayed completely different TCR gene rearrangement sequences between diagnosis and relapse. This indicates that a proportion of very late T-ALL recurrences might represent second T-ALL. Specifically, 88% of clonal rearrangements identified at diagnosis in truly relapsed T-ALL were preserved at relapse. This is significantly higher as compared to previously studied precursor-B-ALL (B70%). Thus, from biological point of view, immunogenotype of T-ALL is more stable as compared with precursor-B-ALL. The overall stability of TCR gene rearrangements was higher in adult T-ALL (97%) than in childhood T-ALL (86%). Based on the stability of TCR gene rearrangements, we propose a strategy for PCR target selection (TCRD þ TAL1-TCRB-TCRG), which probably allows reliable minimal residual disease detection in all T-ALL patients.

Comparative sequence analysis of incomplete DJH and TCR gene rearrangements in children with relapses of T-ALL

“…Finally, there were six patients that relapsed with new clonal PCR targets (four TCRG, four TCRD, three TCRB and one DJH gene rearrangements), which could not be detected at diagnosis even by RQ-PCR using specific primers designed from the relapse sequences (data not shown). In agreement with the observation of Szczepanski et al, 10 we found that the overall stability of clonal rearrangements in T-ALL was significantly higher compared with precursor-B-ALL. Specifically, 83% of original clonal sequences identified at diagnosis were conserved at relapse, compared to 71% found in our previous study on precursor-B-ALL patients.…”

Genome-wide expression analysis of paired diagnosis–relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype

“…[25][26][27][28][29] Clonal rearrangements were subsequently analyzed in the paired relapse sample of the patient by mixed PCR heteroduplex analysis. 30 In all patients who could be evaluated for Ig/TCR gene rearrangements, at least one rearrangement was preserved, indicating that the relapse did not result from de novo leukemia development. If single rearrangements differed between diagnosis and relapse, we assumed that some clonal evolution took place.…”

Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping

“…[37][38][39][40] However, in most patients at least one IG/TCR gene rearrangement is preserved throughout the disease course. [37][38][39][40][41] To reduce the risk of false-negative results, preferably two IG/TCR gene rearrangements should be used as MRD-PCR target. 8 This should be facilitated by supplementing the classical IGH, IGK-Kde, TCRD, and TCRG targets with 'new' MRD-PCR targets, such as Vd2-Ja and TCRB gene rearrangements.…”