title: 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 x 10(-3) and 1 x 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.
authors.affiliation: Children's Cancer Research Institute and St Anna Kinderspital, Vienna, Austria.
authors.forename: Marianne
authors.initials: M
authors.lastname: Konrad
authors.forename: Markus
authors.initials: M
authors.lastname: Metzler
authors.forename: Simon
authors.initials: S
authors.lastname: Panzer
authors.forename: Iris
authors.initials: I
authors.lastname: Ostreicher
authors.forename: Martina
authors.initials: M
authors.lastname: Peham
authors.forename: Reinald
authors.initials: R
authors.lastname: Repp
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.forename: Helmut
authors.initials: H
authors.lastname: Gadner
authors.forename: E Renate
authors.initials: ER
authors.lastname: Panzer-Grumayer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002470:Cell Survival; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000648:ultrastructure*; D002891:Chromosomes, Human, Pair 21 / Q000648:ultrastructure*; D002999:Clone Cells / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011289:Preleukemia / Q000235:genetics / Q000473:pathology*; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D013997:Time Factors; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein