Institut Cochin, Département Développement, Reproduction, Cancer, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.
Leukemia. 2018 Mar;32(3):597-605. doi: 10.1038/leu.2017.284. Epub 2017 Sep 15.
Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.
伴有 FLT3 内部串联重复（FLT3-ITD AML）的急性髓系白血病（AML）占 AML 病例的 20-30%。这种亚型通常对常规治疗反应不佳，并且由于分子旁路机制可能对 FLT3 酪氨酸激酶抑制剂（TKI）产生耐药性。因此，迫切需要针对耐药机制的新治疗策略。Pim 激酶是 FLT3-ITD 致癌靶点，已被牵连到 FLT3 TKI 耐药性中。然而，它们在 FLT3-ITD 下游的精确生物学功能仍需要进一步研究。我们在 Pim2 耗尽的 FLT3-ITD AML 细胞中进行了高通量转录组学和蛋白质组学分析，发现 Pim2 主要通过 Bax 表达和线粒体破坏来控制细胞凋亡。我们鉴定了核糖体蛋白 S6 激酶 A3（RSK2），这是一种 90 kDa 的丝氨酸/苏氨酸激酶，涉及编码 RPS6KA3 基因的丝裂原激活蛋白激酶级联反应。它是 Pim2 的一个新靶点。RSK2 等位基因的异位表达挽救了 Pim2 耗尽细胞的活力，支持 RSK2 在 Pim2 下游的 AML 细胞存活中发挥作用。最后，我们表明 RPS6KA3 敲低减少了体内小鼠中人类 AML 细胞的增殖。我们的结果表明 RSK2 是 Pim2 的一个新靶点，在 FLT3-ITD AML 中具有转化治疗潜力。
