Somatic mutations in myeloid cell leukemia-1 contribute to the pathogenesis of glioma by prolonging its half-life

Abstract

The identification of mutated genes in glioblastoma multiforme (GBM) is an essential step towards improving current understanding of the molecular mechanism underlying the disease and establishing novel targets for diagnostic and therapeutic purposes. The present study used direct sequencing to screen 20 malignancy-associated genes, which have either been well described in the literature or observed multiple times in human cancer sequencing, in cancerous and normal control tissue samples from 20 patients with histologically confirmed GBM. The investigation identified five somatic non-synonymous coding mutations in four candidate genes, with two located in the proline, glutamic acid, serine, threonine-rich region of myeloid cell leukemia sequence 1 (Mcl)-1, (D155G and L174S). The sample pool was then expanded by sequencing Mcl-1 in a further 43 patients with GBM and another somatic mutation in the same region, D155H, was identified. The subsequent functional investigation confirmed that these somatic mutations affected the degradation of Mcl-1, and the growth of glioma cells transfected with mutant plasmids was significantly accelerated compared with cells overexpressing wild-type Mcl-1. The mutational profiling of GBM in the present study revealed for the first time, to the best of our knowledge, several mutations in Mcl-1, and identified this gene as a novel therapeutic target for the treatment of GBM.