Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment. Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism. Overall design: Here, we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation. AML cell line KG1a cells were treated with TAK-981(5µM), VEN(1µM), or both for 48h. DMSO was used as vehicle control (ctrl). Total RNA was purified using miRNeasy RNA isolation kit (Qiagen) then Ribo-Zero RNA-seq was performed.

急性髓系白血病（Acute myeloid leukemia, AML）是一类造血系统恶性肿瘤，以骨髓与外周血中异常未成熟髓系原始细胞的增殖与蓄积为特征。维奈克拉（Venetoclax, VEN）作为选择性B细胞淋巴瘤2（BCL-2）抑制剂，已获美国食品药品监督管理局（FDA）批准，可与低甲基化制剂（hypomethylating agents, HMA）联合用于AML的治疗。然而，治疗失败与治疗耐药仍是临床亟待解决的问题，亟需开发新的治疗策略以克服维奈克拉耐药并增强其抗AML疗效。本研究提出将SUMO化修饰抑制作为一种潜在的新型治疗手段，以满足这一临床需求。小泛素样修饰蛋白（Small Ubiquitin-like MOdifier, SUMO）可通过酶级联反应共价结合至靶蛋白，从而调控靶蛋白的功能。本研究旨在评估SUMO化修饰抑制对维奈克拉抗AML活性的影响，并阐明其潜在作用机制。实验整体设计：本研究采用选择性SUMO激活酶（SAE）抑制剂TAK-981来抑制整体SUMO化修饰。将AML细胞系KG1a分别用5µM TAK-981、1µM维奈克拉，或二者联合处理48小时，以二甲基亚砜（DMSO）作为溶剂对照（ctrl）。采用miRNeasy RNA提取试剂盒（Qiagen）纯化总RNA，随后开展Ribo-Zero RNA测序。