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Acute lymphoblastic leukemia

MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance

Abstract

(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.

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Fig. 1: IL7R signaling mutations and physiological IL7-signaling activates MAPK-ERK signaling in T-ALL.
Fig. 2: Pro-apoptotic BIM is phosphorylated downstream of activated MAPK-ERK signaling.
Fig. 3: Steroid-dependent expression of BIM is not impaired in MAPK-ERK activated cell lines.
Fig. 4: Phosphorylation of BIM directly impairs its binding to anti-apoptotic proteins, which is prevented by pharmacological inhibition of MAPK-ERK signaling.
Fig. 5: MEK-inhibitors synergize with steroid treatment in IL7-dependent and IL7-independent steroid-resistant T-ALL.
Fig. 6: Schematic overview of MAPK-ERK-induced steroid resistance.

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Acknowledgements

This study was sponsored by grants of the foundation “Kinderen Kankervrij”; KiKa-219 (JvdZ), KiKa-92, KiKa-295 (WKS), the Chemotherapy Foundation (AAF) and NIH grants P30 CA013696 (Flow Cytometry Shared Resource and Genomics Shared Resource, Herbert Irving Comprehensive Cancer Center) and R35 CA210065 (AAF). This research was part of the Netherlands X-omics Initiative and partially funded by NWO, project 184.034.019.

Funding

JV and BV: Cancer Research United Kingdom alliance funding from AstraZeneca for SeluDex trial (NCT03705507).

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JvdZ designed study, performed research and wrote paper. JBG, VC, DD, WKS, ZC and JD performed research. GZ, MA, KO, BB, J-PB, JC and AAF performed research, and provided critical input. JV, RP and BV provided critical input and wrote paper. JM designed and supervised the study and wrote paper.

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Correspondence to Jules P. P. Meijerink.

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van der Zwet, J.C.G., Buijs-Gladdines, J.G.C.A.M., Cordo’, V. et al. MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance. Leukemia (2021). https://doi.org/10.1038/s41375-021-01291-5

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