Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations

Gene rearrangements induced by the DNA double-strand cleaving agent neocarzinostatin: conservative non-homologous reciprocal exchanges in an otherwise stable genome

“…Chemotherapy patients treated with DNA topoisomerase II inhibitors often develop secondary leukemias harboring t(4,11) or t (11,15) reciprocal translocations that could arise by misjoining of drug-stimulated, topoisomerase-mediated DSBs. Molecular analysis of translocations in three such leukemias (38,39) revealed highly conservative reciprocal exchanges, similar to those presented here. Intriguingly, t(4,11) translocations in primary leukemias were much more complex, with deletions and duplications of hundreds of base pairs, supporting the view that the simpler chemotherapy-associated translocations were in fact formed by misjoining of drug-induced DSBs.…”

Gene rearrangements induced by the DNA double-strand cleaving agent neocarzinostatin: conservative non-homologous reciprocal exchanges in an otherwise stable genome

“…Chemotherapy patients treated with DNA topoisomerase II inhibitors often develop secondary leukemias harboring t(4,11) or t (11,15) reciprocal translocations that could arise by misjoining of drug-stimulated, topoisomerase-mediated DSBs. Molecular analysis of translocations in three such leukemias (38,39) revealed highly conservative reciprocal exchanges, similar to those presented here. Intriguingly, t(4,11) translocations in primary leukemias were much more complex, with deletions and duplications of hundreds of base pairs, supporting the view that the simpler chemotherapy-associated translocations were in fact formed by misjoining of drug-induced DSBs.…”

Assembly of nuclear matrix–bound protein complexes involved in non‐homologous end joining is induced by inhibition of DNA topoisomerase II

“…On the basis of these data we proposed that illegitimate DNA recombination occurs preferentially at the sites of DNA contact with the nuclear matrix (Razin, 1999). Similar ideas were developed by other authors (Felix, 1998;Ahuja et al, 2000;Lovett et al, 2001;Whitmarsh et al, 2003). In accordance with the proposed model, we demonstrated that the sites of t(8;21) translocations resulting in the fusion of AML-1 and ETO genes (the socalled breakpoint cluster regions, BCRs) are located at the nuclear matrix even in cells with non-rearranged chromosomes 8 and 21 (Iarovaia et al, 2004b).…”

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…Cytostatic agents belonging to the topoisomerase II inhibitors interfere with rejoining of these double-strand breaks, and this activity is believed in some way to increase the risk of two simultaneous, illegitimate recombinations between the broken DNA strands of adjacent chromosomes. Studies of the genomic break-points of cases belonging to pathways III-VI now support this hypothesis, 39,[57][58][59][60][61] as the break points colocalize with topoisomerase II breakage sites.…”

Gene rearrangements induced by the DNA double-strand cleaving agent neocarzinostatin: conservative non-homologous reciprocal exchanges in an otherwise stable genome

“…Chemotherapy patients treated with DNA topoisomerase II inhibitors often develop secondary leukemias harboring t(4,11) or t (11,15) reciprocal translocations that could arise by misjoining of drug-stimulated, topoisomerase-mediated DSBs. Molecular analysis of translocations in three such leukemias (38,39) revealed highly conservative reciprocal exchanges, similar to those presented here. Intriguingly, t(4,11) translocations in primary leukemias were much more complex, with deletions and duplications of hundreds of base pairs, supporting the view that the simpler chemotherapy-associated translocations were in fact formed by misjoining of drug-induced DSBs.…”

Assembly of nuclear matrix–bound protein complexes involved in non‐homologous end joining is induced by inhibition of DNA topoisomerase II

“…On the basis of these data we proposed that illegitimate DNA recombination occurs preferentially at the sites of DNA contact with the nuclear matrix (Razin, 1999). Similar ideas were developed by other authors (Felix, 1998;Ahuja et al, 2000;Lovett et al, 2001;Whitmarsh et al, 2003). In accordance with the proposed model, we demonstrated that the sites of t(8;21) translocations resulting in the fusion of AML-1 and ETO genes (the socalled breakpoint cluster regions, BCRs) are located at the nuclear matrix even in cells with non-rearranged chromosomes 8 and 21 (Iarovaia et al, 2004b).…”

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…Cytostatic agents belonging to the topoisomerase II inhibitors interfere with rejoining of these double-strand breaks, and this activity is believed in some way to increase the risk of two simultaneous, illegitimate recombinations between the broken DNA strands of adjacent chromosomes. Studies of the genomic break-points of cases belonging to pathways III-VI now support this hypothesis, 39,[57][58][59][60][61] as the break points colocalize with topoisomerase II breakage sites.…”

Gene rearrangements induced by the DNA double-strand cleaving agent neocarzinostatin: conservative non-homologous reciprocal exchanges in an otherwise stable genome

“…Chemotherapy patients treated with DNA topoisomerase II inhibitors often develop secondary leukemias harboring t(4,11) or t (11,15) reciprocal translocations that could arise by misjoining of drug-stimulated, topoisomerase-mediated DSBs. Molecular analysis of translocations in three such leukemias (38,39) revealed highly conservative reciprocal exchanges, similar to those presented here. Intriguingly, t(4,11) translocations in primary leukemias were much more complex, with deletions and duplications of hundreds of base pairs, supporting the view that the simpler chemotherapy-associated translocations were in fact formed by misjoining of drug-induced DSBs.…”

Assembly of nuclear matrix–bound protein complexes involved in non‐homologous end joining is induced by inhibition of DNA topoisomerase II

“…On the basis of these data we proposed that illegitimate DNA recombination occurs preferentially at the sites of DNA contact with the nuclear matrix (Razin, 1999). Similar ideas were developed by other authors (Felix, 1998;Ahuja et al, 2000;Lovett et al, 2001;Whitmarsh et al, 2003). In accordance with the proposed model, we demonstrated that the sites of t(8;21) translocations resulting in the fusion of AML-1 and ETO genes (the socalled breakpoint cluster regions, BCRs) are located at the nuclear matrix even in cells with non-rearranged chromosomes 8 and 21 (Iarovaia et al, 2004b).…”

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…Cytostatic agents belonging to the topoisomerase II inhibitors interfere with rejoining of these double-strand breaks, and this activity is believed in some way to increase the risk of two simultaneous, illegitimate recombinations between the broken DNA strands of adjacent chromosomes. Studies of the genomic break-points of cases belonging to pathways III-VI now support this hypothesis, 39,[57][58][59][60][61] as the break points colocalize with topoisomerase II breakage sites.…”