Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone

Abstract

TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/ AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/ AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/ AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 ؋ 10 ؊3 and 1 ؋ 10 ؊4 , respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse. (Blood. 2003; 101:3635-3640)

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

“…In the remaining case (UPN 15) and also in another four cases, we were able to evaluate and confirm that the clonotypic genomic TEL-AML1 fusion sequence, believed to mark the initiated preleukemic clone (8,17,28), was identical at relapse and diagnosis. A prediction of the hypothesis is that TEL deletions, as common but secondary events, should be different in their genomic boundaries at diagnosis and relapse.…”

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

“…37,38 As an added bonus, this technology also provides relevant information about a variety of genetic lesions that characterize several other important TEL/AML1À leukemia subgroups such as those with TEL deletions, AML1 gene amplifications and high hyperdiploid karyotypes, which are hardly retrievable on a routine basis with any other procedure or not visible without adequate metaphase preparations. 21,22,32,40,41 The 25% incidence rate of TEL/AML1 þ cases in our study is in the upper range of the 18-26% reported in RT-PCR screening surveys.…”

“…37,38 In two patients, the respective FISH patterns remained identical, which indicated a genuine reoccurrence of the original leukemic FISH analysis of secondary abnormalities in TEL/AML1 þ ALL A Attarbaschi et al clone. In six patients, on the other hand, the distribution of the secondary abnormalities was different in the diagnostic and relapse samples.…”

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

“…Rapid and sustained disappearance of the dominant leukemia clones and a slow response of the smaller (preleukemic) clones upon first chemotherapy has been observed in t(12;21)-positive ALL patients. 33,34 Combination therapy may fail to eradicate the preleukemic clone, which may, after acquiring a new second leukemogenic hit, give rise to a new leukemia that is (falsely) being interpreted as a relapse of the original leukemia. 35 It is of interest to study whether the early relapses that occur amongst patients without additional genetic abnormalities in TEL or AML1, or with an extra copy of der(21)t(12;21), may be due to other secondary leukemogenic hits rather than the original leukemia.…”