title: The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1.
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.
authors: Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
authors: Kayleigh A
authors: KA
authors: Smith
authors: Ian G
authors: IG
authors: Cowell
authors: Yanming
authors: Y
authors: Zhang
authors: Zbyslaw
authors: Z
authors: Sondka
authors: Caroline A
authors: CA
authors: Austin
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D019457:Chromosome Breakage; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005047:Etoposide / Q000009:adverse effects; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D008969:Molecular Sequence Data; D000075223:Poly-ADP-Ribose Binding Proteins; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000139:chemically induced / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human