RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia
RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia
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DOI：
10.1038/s41375-018-0102-4
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发表时间：
2018-10-01
期刊：
影响因子：
11.4
通讯作者：
Scholl, C.
中科院分区：
文献类型：
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作者：
Rudat, S.;Pfaus, A.;Scholl, C.
许多 AML 病例与 FLT3 等受体酪氨酸激酶 (RTK) 的突变激活有关。然而，RTK 抑制剂作为单一药物的临床疗效有限，表明 AML 是由不同信号分子的同时激活驱动的。我们使用功能基因组方法来鉴定编码 RTK 的 RET 作为 AML 多种亚型中的必需基因，并观察到 AML 细胞通过 ARTN/GFRA3 和 NRTN/GFRA2 配体/共受体复合物激活 RET 信号传导。对下游通路的研究发现，mTORC1 介导的自噬抑制和随后的白血病驱动因素（如突变型 FLT3）的稳定是重要的 RET 效应子。因此，遗传或药理学 RET 抑制会损害 FLT3 依赖性 AML 细胞系的生长，并伴有自噬上调和 FLT3 耗竭。 RET 依赖性在 AML 小鼠模型和原发性 AML 患者样本中也很明显，转录组和免疫组织化学分析发现，相当大比例的 AML 患者中 RET mRNA 水平升高，并且 RET 和 FLT3 蛋白共表达。我们的结果表明，RET-mTORC1 信号传导通过自噬抑制促进 AML，这表明靶向 RET，或者更广泛地说，通过自噬诱导消除白血病驱动因素，为相关的 AML 患者亚群提供了治疗机会。
Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.