title: Emergence of translocation t(9;11)-positive leukemia during treatment of childhood acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Erlangen-Nuremberg, Nuremberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Metzler
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Strissel
authors.forename: Reiner
authors.initials: R
authors.lastname: Strick
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Silja
authors.initials: S
authors.lastname: Roettgers
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.forename: Wolf D
authors.initials: WD
authors.lastname: Ludwig
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Joern D
authors.initials: JD
authors.lastname: Beck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.forename: Reinald
authors.initials: R
authors.lastname: Repp
authors.forename: Thorsten
authors.initials: T
authors.lastname: Langer
mesh_terms: D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure*; D002899:Chromosomes, Human, Pair 9 / Q000648:ultrastructure*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014178:Translocation, Genetic
chemical_list: D004250:DNA Topoisomerases, Type II