title: 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: Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy; Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, Rome, Italy.
authors: Syed Khizer
authors: SK
authors: Hasan
authors: Gianluca
authors: G
authors: Barba
authors: Markus
authors: M
authors: Metzler
authors: Mariadomenica
authors: M
authors: Divona
authors: Tiziana
authors: T
authors: Ottone
authors: Laura
authors: L
authors: Cicconi
authors: Brunangelo
authors: B
authors: Falini
authors: Cristina
authors: C
authors: Mecucci
authors: Francesco
authors: F
authors: Lo-Coco
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy; D056905:Chromosome Breakpoints; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015251:Epirubicin / Q000009:adverse effects; D005260:Female; D056426:Genetic Loci; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects; D015456:Leukemia, Biphenotypic, Acute / Q000139:chemically induced / Q000235:genetics*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D008875:Middle Aged; D008969:Molecular Sequence Data; D005810:Multigene Family; D059003:Topoisomerase Inhibitors / Q000009:adverse effects*; D014178:Translocation, Genetic
chemical_list: D000903:Antibiotics, Antineoplastic; D059003:Topoisomerase Inhibitors; D015251:Epirubicin; D015255:Idarubicin