The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle regulation to Drive Leukemic Transformation [HiC]

Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML. Capture HiC experiment before and after RUNX1/ETO knock-down is used in this study

致癌转录因子（oncogenic transcription factors）如白血病融合蛋白RUNX1/ETO（RUNX1/ETO）是一类癌症特异性但极具挑战性的治疗靶点，其功能依赖于药理学可靶向的下游通路。本研究通过体外/体内RNA干扰（RNAi）筛选，剖析了RUNX1/ETO的转录调控网络，并鉴定出细胞周期蛋白D2（CCND2）为RUNX1/ETO驱动的白血病增殖的关键介导因子。RUNX1/ETO可通过结合CCND2启动子上游的调控元件，促进CCND2的表达。敲低CCND2或使用CDK4/6抑制剂帕博西尼（palbociclib），均可抑制患者来源的急性髓系白血病（AML）细胞的白血病扩增，并损害免疫缺陷小鼠宿主的细胞定植能力。本研究数据证实，RUNX1/ETO通过直接促进细胞周期进程驱动白血病发生，并确立了靶向G1期CCND-CDK复合物作为治疗RUNX1/ETO驱动型急性髓系白血病的极具前景的治疗策略。本研究采用了RUNX1/ETO敲低前后的捕获Hi-C（Capture HiC）实验。