Central role of the mTORC1 pathway in glucocorticoid activity against B-ALL cells

Blood Neoplasia Pub Date : 2024-04-30 DOI:10.1016/j.bneo.2024.100015

Hiroshi Imanaga , Yuichiro Semba , Kensuke Sasaki , Kiyoko Setoguchi , Hillary Maniriho , Takuji Yamauchi , Tatsuya Terasaki , Shigeki Hirabayashi , Fumihiko Nakao , Jumpei Nogami , Shai Izraeli , Koichi Akashi , Takahiro Maeda

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Abstract

Glucocorticoids (GCs), such as dexamethasone and prednisone, are crucial components of B-cell precursor acute lymphoblastic leukemia (B-ALL) therapies. However, the molecular basis of GC-induced cell death remains elusive. Here, we show that GC suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling and that, conversely, oncogenic activation of mTORC1 confers resistance to GCs. Our genome-wide CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) dropout screens reveal that depletion of components of either the gap activity toward Rags 1 or tuberous sclerosis complexes, both negative regulators of mTORC1 signaling, significantly attenuates B-ALL cell sensitivity to dexamethasone. Dexamethasone primarily induces B-ALL cell death by downregulating mTORC1 activity, thus promoting autophagy and impairing protein synthesis. Dexamethasone treatment failed to suppress mTORC1 activity in B-ALL cells expressing mutant GC receptors lacking DNA-binding capacity, suggesting that dexamethasone transcriptionally represses mTORC1 activity. RNA-sequencing analysis identified multiple dexamethasone target genes that negatively regulate mTORC1 activity. Our findings suggest that GC sensitivity is significantly influenced by oncogenic stimuli and/or growth factors that activate the PI3K-AKT-mTORC1 pathway. This is consistent with the frequent GC resistance found in Ph and Ph-like ALLs.

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mTORC1 通路在糖皮质激素抗 B-ALL 细胞活性中的核心作用

摘要糖皮质激素（GCs），如地塞米松和泼尼松，是B细胞前体急性淋巴细胞白血病（B-ALL）疗法的重要组成部分。然而，GC诱导细胞死亡的分子基础仍然难以捉摸。在这里，我们发现 GC 可抑制雷帕霉素复合体 1（mTORC1）的机理靶标信号传导，反之，mTORC1 的致癌激活可使细胞对 GC 产生耐药性。我们的全基因组CRISPR/CRISPR相关蛋白9（CRISPR/Cas9）剔除筛选显示，mTORC1信号转导的负调控因子--间隙活动向雷帕霉素复合体1（gap activity toward Rags 1）或结节性硬化症复合体（tuberous sclerosis complexes）的组分被剔除后，B-ALL细胞对地塞米松的敏感性显著降低。地塞米松主要通过下调 mTORC1 的活性来诱导 B-ALL 细胞死亡，从而促进自噬和影响蛋白质合成。在表达缺乏DNA结合能力的突变GC受体的B-ALL细胞中，地塞米松治疗未能抑制mTORC1的活性，这表明地塞米松转录抑制了mTORC1的活性。RNA测序分析发现了多个地塞米松靶基因，这些基因对mTORC1的活性有负向调节作用。我们的研究结果表明，GC 的敏感性在很大程度上受到激活 PI3K-AKT-mTORC1 通路的致癌刺激和/或生长因子的影响。这与Ph和Ph-like ALLs经常出现的GC耐药性是一致的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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