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Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes

Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2...

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Autores principales: Lomov, Nikolai A., Viushkov, Vladimir S., Ulianov, Sergey V., Gavrilov, Alexey A., Alexeyevsky, Daniil A., Artemov, Artem V., Razin, Sergey V., Rubtsov, Mikhail A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456246/
https://www.ncbi.nlm.nih.gov/pubmed/36077220
http://dx.doi.org/10.3390/ijms23179824
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author Lomov, Nikolai A.
Viushkov, Vladimir S.
Ulianov, Sergey V.
Gavrilov, Alexey A.
Alexeyevsky, Daniil A.
Artemov, Artem V.
Razin, Sergey V.
Rubtsov, Mikhail A.
author_facet Lomov, Nikolai A.
Viushkov, Vladimir S.
Ulianov, Sergey V.
Gavrilov, Alexey A.
Alexeyevsky, Daniil A.
Artemov, Artem V.
Razin, Sergey V.
Rubtsov, Mikhail A.
author_sort Lomov, Nikolai A.
collection PubMed
description Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations.
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spelling pubmed-94562462022-09-09 Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes Lomov, Nikolai A. Viushkov, Vladimir S. Ulianov, Sergey V. Gavrilov, Alexey A. Alexeyevsky, Daniil A. Artemov, Artem V. Razin, Sergey V. Rubtsov, Mikhail A. Int J Mol Sci Article Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility—but not spatial predisposition of the rearrangement partners—plays a major role in the formation of these translocations. MDPI 2022-08-29 /pmc/articles/PMC9456246/ /pubmed/36077220 http://dx.doi.org/10.3390/ijms23179824 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lomov, Nikolai A.
Viushkov, Vladimir S.
Ulianov, Sergey V.
Gavrilov, Alexey A.
Alexeyevsky, Daniil A.
Artemov, Artem V.
Razin, Sergey V.
Rubtsov, Mikhail A.
Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title_full Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title_fullStr Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title_full_unstemmed Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title_short Recurrent Translocations in Topoisomerase Inhibitor-Related Leukemia Are Determined by the Features of DNA Breaks Rather Than by the Proximity of the Translocating Genes
title_sort recurrent translocations in topoisomerase inhibitor-related leukemia are determined by the features of dna breaks rather than by the proximity of the translocating genes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456246/
https://www.ncbi.nlm.nih.gov/pubmed/36077220
http://dx.doi.org/10.3390/ijms23179824
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