PDF(Pubmed)
Abstract：
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.
摘要：
糖皮质激素已经使用了几十年来治疗淋巴瘤，但没有确定的作用机制。使用功能基因组，蛋白质组学，和化学屏幕，我们发现糖皮质激素抑制B细胞受体（BCR）的致癌信号，侵袭性B细胞恶性肿瘤的复发特征，包括弥漫性大B细胞淋巴瘤和伯基特淋巴瘤。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(LAPTM5;KLHL14)和PI3激酶途径(INPP5D;DDIT4)的负调节因子的基因。GR直接抑制CSK的转录，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家族激酶减弱淋巴瘤的组成型BCR信号,引发它们的泛素化和降解。了解到糖皮质激素禁用致癌BCR信号，它们现在可以合理地用于治疗BCR依赖性侵袭性淋巴瘤，并用于构建与BTK抑制剂的机械合理组合方案，PI3激酶，BCL2和CSK。
