Sites de translocations oncogéniques dans le gène MLL: Corrélation avec des sites de clivage par la topoisomérase II cartographiés in vivo au niveau du nucléotide

Abstract

Plusieurs cas de leucémies secondaires impliquant des translocations du gène MLL ont été associés aux traitements de chimiothérapie ayant recours à des inhibiteurs de topoisomérase II (topoII). Des clivages d'ADN induits par ces inhibiteurs, l'étoposide par exemple, ont été suggérés être à l'origine de ces translocations. Une nouvelle technique conçue dans notre laboratoire, l'Extension-Ligation-Mediated PCR (ELM-PCR), a permis de cartographier les sites de clivage produits par la topoII dans une région du bcr (breakpoint cluster region) du gène MLL. Des sites de clivage topoII induits par l'étoposide et des coupures subséquentes reliées à l'induction de l'apoptose ont été cartographiés. Trois sites de clivage par la topoII ont été cartographiés près de deux translocations rapportées dans cette région. Des clivages reliés à l'apoptose ont été détectés à un site où sont localisées 8 des 13 translocations rapportées. La relation entre les sites de clivage observés et les translocations reste à déterminer.

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Several cases of secondary leukemia involving translocations of the MLL gene have been associated with chemotherapy treatments using topoisomerase II (topoII) inhibitors. DNA cleavages induced by these inhibitors, etoposide for example, have been suggested to be the origin of these translocations. A new technique designed in our laboratory, Extension-Ligation-Mediated PCR (ELM-PCR), made it possible to map the cleavage sites produced by topoII in a region of the bcr (breakpoint cluster region) of the MLL gene. Sites of etoposide-induced topoII cleavage and subsequent cleavage linked to the induction of apoptosis were mapped. Three topoII cleavage sites were mapped near two translocations reported in this region. Cleavages linked to apoptosis were detected at a site where 8 of the 13 reported translocations are located. The relationship between the observed cleavage sites and the translocations remains to be determined.