文章：

FLT3-ITD急性髓系白血病对RSK1的依赖性

RSK1 dependency in FLT3-ITD acute myeloid leukemia

原文发布日期：2024-11-26

DOI: 10.1038/s41408-024-01187-4

类型: Article

开放获取: 是

英文摘要：

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.
 

摘要翻译： 

FLT3内部串联重复（FLT3-ITD）是新发急性髓系白血病（AML）中最常见的遗传学改变。本研究鉴定出核糖体蛋白S6激酶A1（RSK1）是FLT3-ITD AML的核心依赖性因子，并揭示其存在关键的双向调控机制。在FLT3-ITD AML细胞系中，干扰RSK1可引发显著细胞凋亡，并消除FLT3及其下游信号通路的磷酸化。通过环己酰亚胺、MG-132及泛素化实验，我们进一步从机制上证明RSK1通过去泛素化酶USP1（我们鉴定的第二依赖性因子）调控FLT3-ITD的活性与蛋白稳定性。重要的是，多变量分析显示RPS6KA1与USP1的高表达与患者不良预后相关，这些效应因子可作为预测FLT3-ITD抑制剂患者生存和治疗反应的生物标志物。最后，采用首创型RSK抑制剂PMD-026（目前正处于乳腺癌Ⅱ期研发阶段）抑制RSK1，能显著减轻MV4-11异种移植模型及同基因型Flt3ITDTet2KO白血病模型的白血病负荷。这些发现为靶向FLT3-ITD白血病提供了一种创新且具有前景的治疗策略。

原文链接：

RSK1 dependency in FLT3-ITD acute myeloid leukemia