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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-10-3252.
Submitted October 28, 2002
Accepted December 10, 2002
Late relapses evolve from slow-responding subclones in t(12;21) positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic Clone
Marianne Konrad, Markus Metzler, Simon Panzer, Iris Oestreicher, Martina Peham, Reinald Repp, Oskar A Haas, Helmut Gadner, and E Renate Panzer-Gruemayer*
Children's Cancer Research Institute, Vienna, Austria
St. Anna Kinderspital, Vienna, Austria
Clinic for Blood Group Serology, University of Vienna, Vienna, Austria
Department of Pediatrics, University of Erlangen, Erlangen, Germany
* Corresponding author; email: renate.panzer{at}ccri.univie.ac.at.
TEL/AML1 positive childhood acute lymphoblastic leukemias (ALL) generally have low risk features, but still about 20% relapse. Our initial molecular genetic analyses in two 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 two patients with late systemic relapses of their TEL/AML1 positive ALL (41 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 two 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 size (5x10-3 and 10-4, respectively), we were able to detect their much slower response to therapy compared to 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 two 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.
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