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. © 2013 Wiley Periodicals, Inc.
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