TEL Deletion Analysis Supports a Novel View of Relapse in Childhood Acute Lymphoblastic Leukemia

Abstract

Purpose: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.Experimental Design: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.Results: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.Conclusions: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.

Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01

“…30 Using microsatellite markers to study TEL gene rearrangements, immunoglobulin or TCR rearrangements, and fluorescence in situ hybridization (FISH) analysis, a number of patients experiencing late relapses had TEL/AML1-positive leukemia derived from, but not identical to, the dominant clone at diagnosis. 31,32 In addition, at least one patient who experienced relapse during therapy developed microsatellite instability in the relapsed subclone of the original leukemia. Taken together, these data support the hypothesis that preleukemic cells harboring the TEL/AML1 fusion gene are not eradicated by initial therapy in some patients who later have relapses.…”

Is the risk of acute lymphoblastic leukemia reduced in siblings to children with the disease? A novel hypothesis explored by international collaboration

“…3 The t(12;21) translocations are functional, but may be balanced by the normal TEL/ETV6 gene. 9 The occurrence and possibly also the timing of subsequent, most likely postnatal, genetic aberrations probably determine, whether a child that carry t(12;21)-positive preleukemic cells will develop ALL. [8][9][10] Exploration of the prenatal origin of childhood leukemia and the significance of the genetic aberrations is critical for the understanding of the natural history of childhood ALL.…”

“…9 The occurrence and possibly also the timing of subsequent, most likely postnatal, genetic aberrations probably determine, whether a child that carry t(12;21)-positive preleukemic cells will develop ALL. [8][9][10] Exploration of the prenatal origin of childhood leukemia and the significance of the genetic aberrations is critical for the understanding of the natural history of childhood ALL. High birth weight, low gestational age and certain in utero exposures have all been related to the risk of ALL, but it is not known whether they exert their effects by being risk factors for the development of preleukemic cells in an otherwise healthy fetus.…”

Cancer Stem Cells in Tumor Heterogeneity

“…In the more classical view of the clonal evolution model, on the other hand, metastases and recurring tumors, given similar selective pressures, are likely to be highly similar to the most advanced clone in the primary tumor. In the relatively few studies dealing with this issue directly to date, interestingly, most of the time the dominant clone at diagnosis differed significantly from the recurring or metastatic lesion's identity (Li et al, 2003;Zuna et al, 2004;Mullighan et al, 2008). These data suggest that the recurring tumor did not evolve directly from the dominant clone at diagnosis, instead, the recurring tumor and the primary tumor likely shared a common ancestor further back in evolution.…”