Clonal Changes Are Frequent in Relapsed TEL-AML1+ ALL and Predominate in Young Children.
Authors: Panzer-Grümayer Renate , Cazzaniga Giovanni , van der Velden Vincent , del Giudice Laura , Peham Martina , Eckert Conny , Schrauder Andre , Harbott Jochen , Basso Guiseppe , Biondi Andrea , van Dongen Jacques , Haas Oskar , Gadner Helmut 
Published: October 2019

Abstract
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.