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Acute myeloid leukemia

CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex

Abstract

The gene encoding the transcription factor C/EBPα is mutated in 10–15% of acute myeloid leukemia (AML) patients. N-terminal CEBPA mutations cause ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is incompletely understood. Here, we demonstrate that the MLL1 histone-methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. Oncogenic C/EBPα p30 and MLL1 show global co-localization on chromatin and p30 exhibits robust physical interaction with the MLL1 complex. CRISPR/Cas9-mediated mutagenesis of MLL1 results in proliferation arrest and myeloid differentiation in C/EBPα p30-expressing cells. In line, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological targeting of the MLL1 complex. Inhibitor treatment impairs proliferation and restores myeloid differentiation potential in mouse and human AML cells with CEBPA mutations. Finally, we identify the transcription factor GATA2 as a direct critical target of the p30-MLL1 interaction. Altogether, we show that C/EBPα p30 requires the MLL1 complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the MLL1 complex. These findings identify the MLL1 complex as a potential therapeutic target in AML with CEBPA mutations.

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Author contributions

L. Schmidt and F.G. designed research; L. Schmidt, E.H., L. Scheiblecker, and F.G. performed experiments and analyzed data; T.E. performed bioinformatic analysis; G.V., J.F., J.G., C.N., and P.V. provided essential material and discussion; L. Schmidt, E.H., L. Scheiblecker, and F.G. wrote the manuscript.

Support

We thank J. Zuber for murine leukemia cells and the RT3REVIN vector and J. Bigenzahn for the LentiGuide-Puro-IRES-GFP vector. NGS was performed at the VBCF NGS Unit (www.vbcf.ac.at). This work was supported by Bloodwise Specialist Programs (Grants 12010 (J.F.) and 13008 (C.N.)), by Medical Research Council Grants G0701761, G0900892 and MC_UU_12009/7 (C.N.), by an Austrian Science Fund (FWF) SFB grant F4704 (P.V.), by the National Institute of Health (NIH) grant R01 (1R01CA160467) (J.G.) and by a grant from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement n° 636855/StG) (F.G.). L. Schmidt is a recipient of a DOC Fellowship of the Austrian Academy of Sciences at the Ludwig Boltzmann Institute for Cancer Research.

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Correspondence to Florian Grebien.

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P.V. received honoraria from Novartis, Incyte, Celgene, and Pfizer and a research grant from Incyte. J.G. receives research support from Kura Oncology, Inc and has an equity ownership in the company. Other coauthors declare that they have no conflict of interest.

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Schmidt, L., Heyes, E., Scheiblecker, L. et al. CEBPA-mutated leukemia is sensitive to genetic and pharmacological targeting of the MLL1 complex. Leukemia 33, 1608–1619 (2019). https://doi.org/10.1038/s41375-019-0382-3

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