Abstract

Mutations of epigenetic regulators are pervasive in human tumors. ASXL1 is frequently mutated in myeloid malignancies. We previously found that ASXL1 forms together with BAP1 a complex that can deubiquitinylate mono-ubiquitinylated lysine 119 on histone H2A (H2AK119ub1), a Polycomb repressive mark. However, a complete mechanistic understanding of ASXL1 in transcriptional regulation and tumor suppression remains to be defined. Here, we find that depletion of Asxl1 confers murine 32D cells to IL3-independent growth at least partly due to sustained activation of PI3K/AKT signaling. Consistently, Asxl1 is critical for the transcriptional activation of Pten, a key negative regulator of AKT activity. Then we confirm that Asxl1 is specifically enriched and required for H2AK119 deubiquitylation at the Pten promoter. Interestingly, ASXL1 and PTEN expression levels are positively correlated in human blood cells and ASXL1 mutations are associated with lower expression levels of PTEN in human myeloid malignancies. Furthermore, malignant cells with ASXL1 downregulation or mutations exhibit higher sensitivity to the AKT inhibitor MK2206. Collectively, this study has linked the PTEN/AKT signaling axis to deregulated epigenetic changes in myeloid malignancies. It also provides a rationale for mechanism-based therapy for patients with ASXL1 mutations.

中文翻译：

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髓系恶性肿瘤中肿瘤抑制性 ASXL1-PTEN/AKT 轴的失调

摘要

表观遗传调节因子的突变在人类肿瘤中普遍存在。ASXL1在髓系恶性肿瘤中经常发生突变。我们之前发现 ASXL1 与 BAP1 一起形成一种复合物，可以去泛素化组蛋白 H2A (H2AK119ub1) 上的单泛素化赖氨酸 119，这是一种 Polycomb 抑制标记。然而，对 ASXL1 在转录调控和肿瘤抑制方面的完整机制理解仍有待确定。在这里，我们发现 Asxl1 的消耗至少部分是由于 PI3K/AKT 信号传导的持续激活，使小鼠 32D 细胞能够独立于 IL3 生长。一致地，Asxl1 对Pten的转录激活至关重要, AKT 活性的关键负调节器。然后我们确认 Asxl1 在Pten启动子处是 H2AK119 去泛素化所必需的。有趣的是，ASXL1 和 PTEN 表达水平在人血细胞中呈正相关，而ASXL1突变与人骨髓恶性肿瘤中 PTEN 的低表达水平相关。此外，具有ASXL1下调或突变的恶性细胞对 AKT 抑制剂 MK2206 表现出更高的敏感性。总的来说，这项研究将 PTEN/AKT 信号轴与髓系恶性肿瘤中失调的表观遗传变化联系起来。它还为ASXL1突变患者的基于机制的治疗提供了基本原理。