Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia: Almost identical MLL breakpoints in therapy-related AML after treatment without etoposides

Thorsten Langer, Markus Metzler, Dirk Reinhardt, Susanne Viehmann, Arndt Borkhardt, Martin Reichel, Martin Stanulla, Martin Schrappe, Ursula Creutzig, Jörg Ritter, Thomas Leis, Ulla Jacobs, Jochen Harbott, Jörn D. Beck, Wolfgang Rascher, Reinald Repp*

*Corresponding author for this work
67 Citations (Scopus)

Abstract

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5′ portions of MLL to a variety of heterologous genes in various 11q23 translocations. AF9 is one of the most common fusion partners of MLL. It spans more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t-AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with cytogenetically diagnosed translocations t(9;11). By use of an optimized multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from each sample was amplified and directly sequenced. In four patients and two cell lines, the AF9 breakpoints were located within BCR1 and in two patients within BCR2, respectively. However, in five patients the AF9 breakpoints were found outside the previously described BCRs within the centromeric region of intron 4 and even within intron 3 in one case. All five patients with a secondary AML, who had not received etoposides during treatment of the primary malignant disease, revealed almost identical MLL breakpoints very close to a breakage hot spot inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence patterns around the breakpoints indicated involvement of a "damage-repair mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute leukemia.

Original languageEnglish
JournalGenes Chromosomes and Cancer
Volume36
Issue number4
Pages (from-to)393-401
Number of pages9
ISSN1045-2257
DOIs
Publication statusPublished - 01.04.2003

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

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