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.

中文翻译：

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RSK2是一种新的Pim2靶标，在FLT3-ITD阳性的急性髓性白血病中具有促生存功能。

具有FLT3内部串联重复（FLT3-ITD AML）的急性髓样白血病（AML）占AML病例的20％至30％。这种亚型通常对常规疗法反应较差，并且由于分子旁路机制而可能对FLT3酪氨酸激酶抑制剂（TKIs）产生抗药性。因此，迫切需要着重于耐药机制的新治疗策略。Pim激酶是FLT3-ITD致癌靶标，与FLT3 TKI抗性有关。但是，它们在FLT3-ITD下游的精确生物学功能需要进一步研究。我们在Pim2缺失的FLT3-ITD AML细胞中进行了高通量的转录组和蛋白质组学分析，发现Pim2主要通过Bax表达和线粒体破坏来控制细胞凋亡。我们确定了核糖体蛋白S6激酶A3（RSK2），一个90 kDa的丝氨酸/苏氨酸激酶，参与由RPS6KA3基因编码的有丝分裂原激活的蛋白激酶级联反应，作为新的Pim2靶标。RPS6KA3等位基因的异位表达挽救了Pim2缺失细胞的生存能力，支持RSK2参与Pim2下游AML细胞存活。最后，我们显示RPS6KA3敲低可减少人类AML细胞在小鼠体内的繁殖。我们的结果表明，RSK2是一种新型的Pim2靶标，在FLT3-ITD AML中具有翻译治疗潜力。我们显示RPS6KA3敲低可减少人类AML细胞在小鼠体内的繁殖。我们的结果表明，RSK2是一种新型的Pim2靶标，在FLT3-ITD AML中具有翻译治疗潜力。我们显示RPS6KA3敲低可减少人类AML细胞在小鼠体内的繁殖。我们的结果表明，RSK2是一种新型的Pim2靶标，在FLT3-ITD AML中具有翻译治疗潜力。