The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1. Issue 2 (5th November 2013)

• Record Type: Journal Article
• Authors: Smith, Kayleigh A.; Cowell, Ian G.; Zhang, Yanming; Sondka, Zbyslaw; Austin, Caroline A.
• Is Part Of: Genes, chromosomes & cancer. Volume 53:Issue 2(2014:Feb.)
• Page Start: 117
• Page End: 128
• Publication Date: 2013-11-05
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22124
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Rearrangements involving the <italic>RUNX1</italic> 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 <italic>RUNX1‐RUNX1T1</italic> t‐AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t‐AML patients with the <italic>RUNX1</italic>‐ <italic>RUNX1T1</italic> translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of <italic>RUNX1</italic> chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on <italic>RUNX1</italic> and <italic>RUNX1T1</italic> chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on <italic>RUNX1</italic> where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between <italic>RUNX1</italic> and two translocation partners (<italic>RUNX1T1</italic> and <italic>EVI</italic>) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B‐dependent increase in the number of nuclei displaying juxtaposed <italic>RUNX1</italic> and <italic>RUNX1T1</italic> loci following etoposide treatment. © 2013 Wiley Periodicals, Inc.</p> </abstract>