RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia

Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151. Overall design: Examination of the epigenetic and transcriptomic changes in T-ALL cell lines following NOTCH1 inhibition and RUNX1 knockdown.

Runt相关转录因子1（RUNX1）在多种白血病及上皮细胞癌中具有致癌性，其表达与不良预后密切相关。现有研究模型表明，RUNX1可与其他致癌因子（如NOTCH1、TAL1）协同，驱动T细胞急性淋巴细胞白血病（T-ALL）中原癌基因的表达，但RUNX1所调控的分子机制及其与其他因子的协同作用仍未明确。对RUNX1与NOTCH1进行抑制后的整合染色质与转录组分析显示，RUNX1在维持全基因组H3K27ac水平方面具有出乎意料的广泛作用，且NOTCH1需依赖RUNX1才能实现对包括MYC、DTX1、HES4、IL7R及NOTCH3在内的NOTCH1关键靶基因的协同转录激活。超级增强子对RUNX1敲低具有优先敏感性，而经泛BET抑制剂I-BET151处理后，依赖RUNX1的超级增强子会被破坏。整体实验设计：探究T-ALL细胞系经NOTCH1抑制与RUNX1敲低后的表观遗传与转录组变化。