ETV6/RUNX1 abrogates mitotic checkpoint function and targets its key player MAD2L1

Krapf, G., Kaindl, U., Kilbey, A., Fuka, G., Inthal, A., Joas, R., Mann, G., Neil, J.C. , Haas, O.A. and Panzer-Grümayer, E.R. (2010) ETV6/RUNX1 abrogates mitotic checkpoint function and targets its key player MAD2L1. Oncogene, 29(22), pp. 3307-3312. (doi: 10.1038/onc.2010.53)

Abstract

Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC). Consistent with this notion, E/R-expressing diploid murine and human cell lines have decreased proportions of cells with 4N DNA content and a lower mitotic index when treated with spindle toxins. Moreover, both RUNX1 and E/R regulate mitotic arrest-deficient 2 L1 (MAD2L1), an essential MC component, by binding to promoter-inherent RUNX1 sites, which results in down-regulation of MAD2L1 mRNA and protein in E/R-expressing cells. Forced expression of E/R also abolishes RUNX1-induced reporter activation, whereas E/R with a mutant DNA-binding site leads to only minor effects. Our data link for the first time E/R, MC, and MAD2L1 and provide new insights into the function of the E/R fusion gene product. Although tetraploidy is an almost exclusive feature of E/R-positive leukemias, its rarity within this particular subgroup implies that further yet unknown factors are required for its manifestation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Neil, Professor James and Kilbey, Dr Anna
• Authors: Krapf, G., Kaindl, U., Kilbey, A., Fuka, G., Inthal, A., Joas, R., Mann, G., Neil, J.C., Haas, O.A., and Panzer-Grümayer, E.R.
• Subjects: Q Science > QR Microbiology > QR355 Virology
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Oncogene
• ISSN: 0950-9232