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Emergence of translocation t(9;11)-positive leukemia during treatment of childhood acute lymphoblastic leukemia.

Metzler M, Strissel PL, Strick R, Niemeyer C, Roettgers S, Borkhardt A, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Reinhardt D, Creutzig U, Beck JD, Rascher W, Repp R, Langer T

Department of Pediatrics, University of Erlangen-Nuremberg, Nuremberg, Germany.

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.

Published 30 August 2004 in Genes Chromosomes Cancer, 41(3): 291-6.
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