BMI1 抑制诱导衰老，是 H3K27M 突变型弥漫性内生型脑桥胶质瘤的治疗弱点。
Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG.
机构信息
Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
出版信息
Cell Rep. 2020 Oct 20;33(3):108286. doi: 10.1016/j.celrep.2020.108286.
Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种无法治愈的儿童脑肿瘤，其特征是组蛋白赖氨酸 27 发生突变，导致表观基因组失调。目前尚未开发出针对这种肿瘤的有效治疗方法。我们使用针对表观基因组调节剂的 RNAi 和化学筛选的组合，鉴定出多梳抑制复合物 1（PRC1）成分 BMI1 是体内 DIPG 肿瘤维持的关键因素。BMI1 染色质占据在与 DIPG 细胞分化和肿瘤抑制因子相关的基因上富集。抑制 BMI1 会由于诱导衰老而降低细胞自我更新并减弱肿瘤生长。长期抑制 BMI1 会诱导衰老相关的分泌表型，从而促进肿瘤复发。使用 BH3 蛋白模拟物清除衰老细胞与 BMI1 抑制协同作用，增强体内肿瘤细胞的杀伤作用。
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