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Molecular targets for therapy

Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Abstract

Mutations in SET-binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.

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Fig. 1: SETBP1D868N enhances the proliferation of NRASG12D and PTPN11E76K hematopoietic progenitors.
Fig. 2: SETBP1D868N enhances MAPK signaling driven by NRASG12D.

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Acknowledgements

Research reported in this publication was supported by NCI F32CA239422 to SAC, as well as a Knight Pilot Award, American Society of Hematology Scholar Award, and Gilead Research Scholars Program in Hematology/Oncology to JEM. The authors gratefully acknowledge the support of the OHSU Flow Cytometry Shared Resource, with particular regard to operators Brianna Garcia and Dorian LaTocha.

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Contributions

Concept and design: SAC, TPB, and JEM. In vitro experiments: SAC, CC, ZS, BMS, LM, ACF, and JEM. In vivo experiments: SAC and ZS. Analysis and interpretation of data: SAC, TPB, RC, and JEM. Writing, review, and revision of the manuscript: SAC, TPB, CC, RC, ZS, BMS, LM, ACF, and JEM.

Corresponding author

Correspondence to Julia E. Maxson.

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Conflict of interest

NCI F32CA239422 to SAC; Knight Pilot Award, Gilead Hematology/Oncology Research Scholars Award and American Society of Hematology Scholar Award to JEM. JEM is the recipient of a career development grant from Gilead Sciences. The other authors declare no potential conflict of interest.

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Carratt, S.A., Braun, T.P., Coblentz, C. et al. Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia. Leukemia (2021). https://doi.org/10.1038/s41375-021-01278-2

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