Repositioning of ETO gene in cells treated with VP-16, an inhibitor of DNA-topoisomerase II.
The translocation t(8;21)(q22;q22) affecting AML1 and ETO genes is known to be one of the frequent chromosome translocations in acute myeloid leukemia. But no data have been available up to date concerning mutual positioning of these particular genes in the nucleus of a living cell as well as the mechanism of their rapprochement and realignment. Here we show that there is no proximity between these two genes in the primary nuclei of normal human male fibroblasts and moreover that these genes are located in different nuclear layers. But we further show that treatment of cells with VP-16 (etoposide), an inhibitor of DNA topoisomerase II widely used in anticancer chemotherapy, causes the ETO gene repositioning which allows AML1 and ETO genes to be localized in the same nuclear layer. Inhibitor studies demonstrate that such an effect is likely to be connected with the formation of stalled cleavable complexes on DNA. Finally, inhibition of ETO gene repositioning by 2,3-butanedione monoxime (BDM) suggests that this process depends on nuclear myosin. Together, our data corroborate the so called "breakage first" model of the origins of recurrent reciprocal translocation.
Rubtsov
Mikhail A
MA
Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology of the Russian Academy of Sciences, 34/5 Vavilov Street, 119334 Moscow, Russia.
Terekhov
Sergey M
SM
Razin
Sergey V
SV
Iarovaia
Olga V
OV
D002467:Cell Nucleus; D019457:Chromosome Breakage; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology*; D005347:Fibroblasts; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D009218:Myosins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D005047:Etoposide; D009218:Myosins