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Acute myeloid leukemia

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia

Abstract

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.

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Acknowledgements

This work was supported by grants from the Institut National du Cancer (Projet Recherche Translationnelle TRANSLA13-087) and from the Ligue Nationale Contre le Cancer (Equipe Labellisée EL2014; Projet R14077KK).

Author contributions

Contribution: M-AH, AJ, FM, JM, RB, ASG, ML, JD, LP and NJ performed in vitro experiments; ES and CL performed in vivo experiments; E-FG, VS and MLG performed proteomic experiments; OK and MF performed sequencing experiments; PS analyzed the results and wrote the paper; CR, PA, PM and DB analyzed the results; J-ES designed the in vivo research and wrote the paper; JT designed the research, made the figures and wrote the paper.

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Correspondence to J Tamburini.

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Hospital, MA., Jacquel, A., Mazed, F. et al. RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia. Leukemia 32, 597–605 (2018). https://doi.org/10.1038/leu.2017.284

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