Age-related patterns of immunoglobulin and T-cell receptor gene rearrangements in precursor-B-ALL: implications for detection of minimal residual disease.

Abstract

Detailed Southern blot and PCR analysis of Ig heavy (IGH), Ig kappa (IGK), T-cell receptor delta (TCRD), and TCR gamma (TCRG) genes were performed in 289 children with precursor-B-ALL in order to determine age-related Ig/TCR patterns and their implications for detection of minimal residual disease (MRD). Overall, IGH, IGK, TCRD, and TCRG gene rearrangements were detected in 98, 62, 90, and 58% of patients, respectively. The frequency of IGH and TCRD rearrangements was independent of rearrangements in one of the other three loci, whereas Ig kappa deleting element and TCRG rearrangements preferentially coincided. Southern blot analysis showed that oligoclonality of IGH, IGK, and TCRD was interrelated, that is, oligoclonality in one locus was related with a higher chance of oligoclonality in another locus. Combined Southern blot and PCR analysis revealed that Ig/TCR patterns were age related: children younger than 3 years or older than 10 years showed a higher prevalence of incomplete IGH rearrangements and a lower prevalence of IGK deletions, TCRG rearrangements, and TCRD rearrangements than children between 3 and 10 years. In addition, IGH oligoclonality was more frequent in the younger and older children. These age-related differences probably reflect ALL subsets with different cellular origin and differences in the duration of the preleukemic phase between the initial and final leukemogenetic hit. The more immature Ig/TCR gene rearrangement pattern in children younger than 3 years or older than 10 years resulted in relatively low numbers of potential MRD-PCR targets per patient, particularly if only monoclonal rearrangements were taken into account. These data provide insight into the immunobiological characteristics of Ig/TCR gene rearrangements in childhood precursor-B-ALL and form a useful basis for designing improved strategies for the identification and selection of MRD-PCR targets.