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.
Hasan, S.k., Barba, G., Metzler, M., Divona, M., Ottone, T., Cicconi, L., et al. (2014). Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23). GENES, CHROMOSOMES & CANCER, 53(3), 248-254 [10.1002/gcc.22135].
|Tipologia:||Articolo su rivista|
|Citazione:||Hasan, S.k., Barba, G., Metzler, M., Divona, M., Ottone, T., Cicconi, L., et al. (2014). Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23). GENES, CHROMOSOMES & CANCER, 53(3), 248-254 [10.1002/gcc.22135].|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/gcc.22135|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2014|
|Titolo:||Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23)|
|Autori:||Hasan, Sk; Barba, G; Metzler, M; Divona, M; Ottone, T; Cicconi, L; Falini, B; Mecucci, C; Lo Coco, F|
|Appare nelle tipologie:||01 - Articolo su rivista|