Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
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γ-分泌酶抑制剂（GSI）阻断T细胞急性淋巴细胞白血病（T-ALL）中致癌NOTCH 1的激活。然而，有限的抗白血病细胞毒性和严重的胃肠道毒性限制了这些靶向药物的临床应用。在这里，我们表明，GSIs加糖皮质激素的联合治疗可以提高GSIs的抗白血病作用，并降低其体内肠道毒性。在糖皮质激素耐药的T-ALL中抑制NOTCH 1信号传导恢复糖皮质激素受体的自动上调，并通过诱导BIM表达诱导凋亡性细胞死亡。GSI处理导致细胞周期停滞和杯状细胞在肠道中的积累，这是由Klf 4的上调介导的，Klf 4是杯状细胞分化所需的细胞周期的负调节因子。相比之下，糖皮质激素治疗诱导Ccnd 2的转录上调，并保护小鼠免于发展肠杯状细胞化生，肠杯状细胞化生通常由GSI抑制NOTCH信号传导诱导。这些结果支持糖皮质激素联合GSI在治疗糖皮质激素耐药T-ALL中的作用。
Gamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.
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