Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK.

中文翻译：

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糖皮质激素的分子靶点阐明其对侵袭性淋巴瘤的治疗功效

糖皮质激素已被用于治疗淋巴瘤数十年，但尚未确定作用机制。通过功能基因组、蛋白质组和化学筛选，我们发现糖皮质激素可抑制 B 细胞受体 (BCR) 的致癌信号传导，这是侵袭性 B 细胞恶性肿瘤（包括弥漫性大 B 细胞淋巴瘤和伯基特淋巴瘤）的复发特征。糖皮质激素诱导糖皮质激素受体 (GR) 直接反式激活编码 BCR 稳定性负调节因子（LAPTM5；KLHL14）和 PI3 激酶通路（INPP5D；DDIT4）的基因。 GR 直接抑制 CSK 的转录，CSK 是一种限制 BCR 近端 Src 家族激酶活性的激酶。 CSK 抑制通过过度激活 Src 家族激酶来减弱淋巴瘤的组成型 BCR 信号传导，触发其泛素化和降解。了解糖皮质激素会禁用致癌的 BCR 信号传导后，现在可以合理地使用它们来治疗 BCR 依赖性侵袭性淋巴瘤，并用于与 BTK、PI3 激酶、BCL2 和 CSK 抑制剂构建机械上合理的联合治疗方案。