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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2019

AutorInnen: Schmidt, L; Heyes, E; Scheiblecker, L; Eder, T; Volpe, G; Frampton, J; Nerlov, C; Valent, P; Grembecka, J; Grebien, F

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

Quelle: Leukemia. 2019; 33(7):1608-1619



Autor/innen der Vetmeduni Vienna:

Eder Thomas
Grebien Florian
Heyes Elizabeth Claire
Schmidt Luisa

Beteiligte Vetmed-Organisationseinheiten
Institut für Medizinische Biochemie


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.

Keywords Pubmed: CCAAT-Enhancer-Binding Protein-alphagenetics
CRISPR-Cas Systems
Cell Differentiation
Cell Proliferation
GATA2 Transcription Factor
Hematopoiesis
Histone-Lysine N-Methyltransferaseantagonists & inhibitorsgeneticsmetabolism
Humans
Leukemia, Myeloid, Acutedrug therapygeneticspathology
Mutation
Myeloid-Lymphoid Leukemia Proteinantagonists & inhibitorsgeneticsmetabolism
Protein Interaction Domains and Motifsdrug effects
Proto-Oncogene Proteinsmetabolism
Small Molecule Librariespharmacology
Tumor Cells, Cultured

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