Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23).

Abstract

Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.

• Authors: Syed Khizer Hasan, Gianluca Barba, Markus Metzler, Mariadomenica Divona, Tiziana Ottone, Laura Cicconi, Brunangelo Falini, Cristina Mecucci, Francesco Lo-Coco
• Journal: Genes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 53 Issue 3 Pg. 248-54 (Mar 2014) ISSN: 1098-2264 [Electronic] United States
• PMID: 24310817 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Topoisomerase Inhibitors
• Epirubicin
• Idarubicin

Topics

• Antibiotics, Antineoplastic (adverse effects)
• Base Sequence
• Breast Neoplasms (drug therapy)
• Carcinoma, Ductal, Breast (drug therapy)
• Chromosome Breakpoints
• Chromosomes, Human, Pair 11 (genetics)
• Chromosomes, Human, Pair 4 (genetics)
• Epirubicin (adverse effects)
• Female
• Genetic Loci
• Humans
• Idarubicin (adverse effects)
• Leukemia, Biphenotypic, Acute (chemically induced, genetics)
• Leukemia, Promyelocytic, Acute (drug therapy)
• Middle Aged
• Molecular Sequence Data
• Multigene Family
• Topoisomerase Inhibitors (adverse effects)
• Translocation, Genetic