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The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1

Lookup NU author(s): Kayleigh Smith, Dr Ian Cowell, Dr Zbyslaw Sondka, Professor Caroline Austin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment. (c) 2013 Wiley Periodicals, Inc.


Publication metadata

Author(s): Smith KA, Cowell IG, Zhang YM, Sondka Z, Austin CA

Publication type: Article

Publication status: Published

Journal: Genes Chromosomes & Cancer

Year: 2014

Volume: 53

Issue: 2

Pages: 117-128

Print publication date: 01/02/2014

Online publication date: 05/11/2013

Acceptance date: 10/10/2013

Date deposited: 29/08/2014

ISSN (print): 1045-2257

ISSN (electronic): 1098-2264

Publisher: Wiley-Blackwell Publishing

URL: http://dx.doi.org/10.1002/gcc.22124

DOI: 10.1002/gcc.22124


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