除了已知癌症驱动基因中的许多其他突变外，套细胞淋巴瘤 (MCL) 的特点是磷酸肌醇 3 激酶 (PI3K) 级联的重要调节因子的反复遗传改变，包括 PIK3CA 增加和 PTEN 损失。为了评估 MCL 中这些畸变的生物学和功能后果，我们引入了 PIK3CA (PIK3CA UP) 的转基因表达，并在 5 个 MCL 细胞系中进行了 PTEN 基因 (PTEN KO / KD) 的敲除/敲低。对修饰后的细胞系进行了相关表型测试，包括对上游 B 细胞受体 (BCR) 信号传导的依赖性（通过额外的 BCR 敲除）。 PIK3CA 过表达降低了所测试的 MCL 对 BCR 促生存信号传导的依赖性，降低了氧化磷酸化水平，并增加了对 2-脱氧葡萄糖（一种糖酵解抑制剂）的抵抗力。 AKT 磷酸化状态不变以及对 PI3K 抑制剂电池的敏感性不变表明 PIK3CA 增益可能以不依赖 AKT 的方式影响 MCL 细胞。 PTEN KO 与更独特的表型相关：AKT 过度磷酸化和过度激活、对多种抑制剂（大多数测试的 PI3K 抑制剂、BTK 抑制剂依鲁替尼和 BCL2 抑制剂 Venetoclax）的耐药性增加、糖酵解速率增加以及对 2-脱氧葡萄糖的耐药性，并显着降低对促生存 BCR 信号传导的依赖。我们的结果表明，PI3K 通路的频繁畸变可能会重新连接相关信号，从而降低 MCL 中对 BCR 信号的依赖性、更好的代谢和缺氧适应以及靶向治疗耐药性。版权所有 © 2024 美国血液学会。

Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO / KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged AKT phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might impact MCL cells in AKT independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, BTK inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.Copyright © 2024 American Society of Hematology.