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Purpose: Variations of the immunogenotype and TEL deletions in children with TEL-AML1+ acute lymphoblastic leukemia support the hypothesis that relapses derive from a persistent TEL-AML1+ preleukemic/leukemic clone rather than a resistant leukemia.We aimed at elucidating the relationship between the immunogenotype patterns at diagnosis and relapse as well as their clinical and biological relevance. Patients and Methods: Immunoglobulin and T-cell receptor gene rearrangements were analyzed in 41 children with a TEL-AML1+ acute lymphoblastic leukemia and an early (up to 30 months after diagnosis; n = 12) or late (at 30 months or later; n = 29) disease recurrence by a standardized PCR approach. Results: In 68% of the patients (group I), we identified differences in the immunogenotype patterns, whereas no changes were observed in the remaining 32% (group II). The divergence resulted more often from clonal selection than clonal evolution and consisted predominantly of losses (0-6, median 5) and/or gains (0-4, median 1) of rearrangements. The frequency and number of clonal immunoglobulin/T-cell receptor rearrangements in group I was higher at diagnosis (2-13, median 5) than at relapse (2-7, median 4), whereas it was the lowest in group II (1-5, median 3). Although group I children were younger at diagnosis, there was no correlation between particular immunogenotype patterns and remission duration. Conclusion: These findings imply that the clonal heterogeneity in younger children most likely reflects an ongoing high recombinatorial activity in the preleukemic/leukemic cells, whereas the more uniform repertoire observed in older children mirrors end-stage rearrangement patterns of selected cell clones that evolved during the prolonged latency period.With a frequency of f25%, the translocation t(12;21) (p13;q22) and its molecular genetic counterpart, the TEL-AML1 gene fusion, is the most common specific genetic rearrangement in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The initial view that this rearrangement concurs with an extraordinarily favorable prognosis has recently become a matter of discussion because in several therapy studies the incidence of TEL-AML1+ cases at diagnosis and relapse was found to be similar (reviewed in ref. 1).The TEL-AML1 gene fusion is an early, or perhaps even the first, event in leukemia development. It commonly occurs already during fetal development but it is considered insufficient to cause clinically overt leukemia by itself (2). Further events are required but seem to be rare because the incidence of Authors' Affiliations:

The detection of minimal residual disease (MRD) during the first\ud phase of treatment can predict outcome in childhood acute\ud lymphoblastic leukemia (ALL).1 Currently MRD detection in ALL\ud patients provides important information in order to assign a\ud tailored-treatment and the risk of an impending relapse. Nevertheless,\ud the major treatment failure in ALL occurs predominantly\ud in patients with T-cell ALL. This reflects especially a more\ud therapy-resistance and a slower clearance of blasts of T-ALL in\ud comparison with precursor-B-ALL.2 Therefore, the quantification\ud of early response to therapy and the monitoring of MRD\ud during and after treatment can greatly improve the outcome and\ud long-term quality of life of these patients. In childhood ALL,\ud detection of MRD with high sensitivity (ie 104, 105) can be\ud achieved by quantitative PCR methods (RQ-PCR) of rearranged\ud immunoglobulin (Ig) and T-cell receptor (TCR) genes.1,3 The\ud usefulness of these specific PCR targets should give attention to\ud the possible modification of Ig and TCR gene rearrangements that\ud could occur during the course of disease, due to continue activity\ud of the V(D)J recombinase enzymes in leukemic blast

The TEL-AML1 fusion gene is present in 25% of childhood B cell precursor ALL and arises generally in utero. Depending on the treatment protocol up to 20% of patients relapse, which represents the highest absolute number of relapses in a genetically well-defined subgroup. As proposed previously, a significant proportion of these relapses seem to derive from a persistent ancestral TEL-AML1+ clone. This notion is based on the observation of different deletions of the non-rearranged TEL allele as well as unrelated clonotypic Ig/TCR rearrangements at diagnosis and relapse. As an extension of these studies, we analyzed the IGH, IGK, TCRD and TCRG gene rearrangements from samples obtained from 41 children with TEL-AML1+ ALL at diagnosis and relapse. Our aim was to determine the development of clonal changes during the course of the diseases and to investigate their potential biological and clinical significance. Based on the immunogenotype at diagnosis and relapse, we divided the patients into two groups. Group I (n=13) consisted of patients with identical Ig/TCR rearrangements, whereas group II (n=28) included those with a change in their immunogenotype. These differences derived either from clonal evolution (32%) or clonal selection (68%) and resulted mainly from losses (0–6, median 5) and/or gains (0–4, median 1) of rearrangements. The number of rearrangements at diagnosis per case also differed (p=0.003) between the two groups (1–5, median 3 in group I; 2–13, median 5 in group II). With regard to individual gene loci, we observed the highest frequency of rearrangements at the IGH (86%) and TCRD (68%) loci in group II at diagnosis, whereas at the corresponding relapses it was only 79% at IGH and 39% at TCRD (p=0.004). The incidence of IGK and TCRG rearrangements was equally high at both occasions (86% and 93%, respectively). The incidence of rearranged loci in group I, on the other hand, concurred with that of the relapse samples of group II. Of special interest is also the fact that the patients of group I were older at diagnosis than those of group II (4.9 versus 3.1 yrs), which is in accordance with our earlier report on age-related variations of Ig/TCR rearrangements. We thus conclude that i) changes in the immunogenotype take place in the majority of children with relapses of a TEL-AML1+ ALL, ii) children with a change in their immunogenotype are younger at initial diagnosis than those with a conserved immunogenotype and iii) there is no association between the immunogenotype patterns and the duration of first remission. We therefore propose that the greater clonal diversity in younger children mirrors the result of a high recombinatorial activity, while the restricted repertoire in older children reflects end-stage patterns due to ongoing recombination/deletion and selection processes during their prolonged latency period. Finally, the likelihood of stability of the various rearrangements (IGK 81%, TCRG 70%, IGH 62% and TCRD 47%) can be used as a hierarchical guideline for MRD studies.