CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias [ATAC-Seq]

Acute myeloid leukemias (AMLs) have an overall poor prognosis and many high-risk cases co-opt stem cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem cell-like states by directly repressing pro-differentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-interacting regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for MECOM-driven leukemogenesis. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo, suggesting a broadly applicable differentiation-based approach for improving therapy. ATAC-seq profiling of MECOM-FKBP12F36V cell lines (MUTZ-3, UCSD-AML1, HNT-34, and OCI-AML4) treated with 500nM dTAGV-1 or DMSO during in vitro culture.

急性髓系白血病（AMLs）整体预后不良，多数高危病例会劫持干细胞基因调控程序，但其具体调控机制仍不甚明晰。干细胞转录因子MECOM的异常高表达，是多数难治性急性髓系白血病的关键驱动机制之一，但MECOM如何介导这类侵袭性AML表型的产生，目前仍未阐明。为突破现有实验研究的局限性，我们构建并应用了结合功能基因组读值的靶向蛋白质降解技术，通过实验证实MECOM可通过直接抑制促分化基因调控程序，促进恶性干细胞样细胞状态的形成。令人意外的是，该调控网络中的单个节点——位于髓系分化调控因子CEBPA下游42kb处的MECOM互作调控元件，不仅是MECOM驱动白血病发生所必需的，同时也足以诱导白血病发生。尤为重要的是，靶向激活该调控元件可促进这类侵袭性AML的细胞分化，并在体内降低白血病负荷，这提示一种可广泛应用的基于分化疗法的策略以改善治疗效果。本数据集包含体外培养条件下，经500nM dTAGV-1或二甲基亚砜（DMSO）处理的MECOM-FKBP12F36V细胞系（包括MUTZ-3、UCSD-AML1、HNT-34及OCI-AML4）的ATAC-seq（转座酶可及性测序）谱分析数据。