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.

Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement

“…18,20,23,24,26,41,42 We demonstrated that infant ALL patients of 0-6 months of age at diagnosis as compared to older infants (6-12 months) showed a more immature Ig/TCR pattern, particularly characterized by a high prevalence of incomplete IGH gene rearrangements and low frequencies of complete IGH, IGK and TCRD gene rearrangements (Figure 4). Infants with MLL-AF4 were more prevalent in the youngest age groups, whereas older infant leukemias more frequently lacked a rearranged MLL gene.…”

“…[23][24][25] Within infant ALL, different Ig/TCR patterns were observed, depending on age of the infant at diagnosis, immunophenotype (CD10 expression) and particularly depending on the presence and type of MLL rearrangement. Immature Ig/TCR gene rearrangements were found in MLL-AF4 and MLL-ENL-positive infant ALL patients, which generally presented at young age (0-6 months) with a CD10-negative ALL.…”

“…Ig and TCR gene rearrangements in infant ALL cases were compared with the same rearrangements in 274 recently reported childhood precursor-B-ALL cases (X1 year at diagnosis) 23,25 (Table 1). These data demonstrate that the frequency of IGK, TCRB (Vb-Db-Jb), TCRG and TCRD gene rearrangement in infant ALL is significantly lower compared to childhood precursor-B-ALL (Po0.05).…”

“…[33][34][35][36] Ig and TCR gene rearrangements in infant ALL cases were compared with the same rearrangements recently reported in 274 childhood precursor-B-ALL cases (41 year at diagnosis). [23][24][25] Southern blot analysis of Ig/TCR gene rearrangements Southern blot analysis was performed in 74 of 135 infant ALL cases (55%) for IGH and TCRD gene rearrangements and in 61 out of 135 infant cases (45%) for IGK-Kde gene rearrangements. Southern blot analysis was performed using BglII-digested DNA in combination with IGHJ6, TCRDJ1 and/or IGKDE probes (DAKO Corporation, Carpinteria, CA, USA).…”

“…It has previously been shown in childhood precursor B-ALL that Ig/TCR gene rearrangement patterns are related with age [23][24][25] as well as the presence of TEL-AML1 fusion gene transcripts. 26 Therefore, we aimed to perform detailed analysis of Ig/TCR gene rearrangements in 133 infant ALL cases to investigate whether Ig/TCR gene rearrangement patterns were related to the presence and type of MLL rearrangement, immunophenotype (CD10 expression) and age at diagnosis.…”