期刊
ONCOGENE
卷 29, 期 22, 页码 3307-3312出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.53
关键词
ETV6/RUNX1; t(12;21); acute lymphoblastic leukemia; mitotic checkpoint MAD2L1; tetraploidy
资金
- FWF [P17551-B14]
- Austrian Ministry for Education, Science and Culture
- St Anna Kinderkrebsforschung
- Leukaemia Research Fund
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. Oncogene (2010) 29, 3307-3312; doi: 10.1038/onc.2010.53; published online 1 March 2010
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