Fleming Travis J, Antoszewski Mateusz, Lambo Sander, Gundry Michael C, Piussi Riccardo, Wahlster Lara, Shah Sanjana, Reed Fiona E, Dong Kevin D, Paulo Joao A, Gygi Steven P, Mimoso Claudia, Goldman Seth R, Adelman Karen, Perry Jennifer A, Pikman Yana, Stegmaier Kimberly, Barrachina Maria N, Machlus Kellie R, Hovestadt Volker, Arruda Andrea, Minden Mark D, Voit Richard A, Sankaran Vijay G
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
bioRxiv. 2024 Dec 30:2024.12.30.630680. doi: 10.1101/2024.12.30.630680.
Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting 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-bound -regulatory element located 42 kb downstream of the myeloid differentiation regulator , is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden , suggesting a broadly applicable differentiation-based approach for improving therapy.
急性髓系白血病（AML）总体预后较差，许多高危病例会采用干细胞基因调控程序，但其发生机制仍知之甚少。干细胞转录因子MECOM的表达增加是大多数无法治愈的AML的一个关键驱动机制。MECOM如何导致这种侵袭性AML表型仍不清楚。为了解决现有的实验局限性，我们设计并应用了具有功能基因组读数的靶向蛋白质降解技术，以证明MECOM通过直接抑制促分化基因调控程序来促进恶性干细胞样状态。值得注意的是，出乎意料的是，该网络中的一个节点，即位于髓系分化调节因子下游42 kb处的一个与MECOM结合的调控元件，对于维持MECOM驱动的白血病既必要又充分。重要的是，该调控元件的靶向激活促进了这些侵袭性AML的分化并减轻了白血病负担，这表明一种广泛适用的基于分化的治疗方法有望改善治疗效果。
