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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2015

AutorInnen: Grebien, F; Vedadi, M; Getlik, M; Giambruno, R; Grover, A; Avellino, R; Skucha, A; Vittori, S; Kuznetsova, E; Smil, D; Barsyte-Lovejoy, D; Li, F; Poda, G; Schapira, M; Wu, H; Dong, A; Senisterra, G; Stukalov, A; Huber, KVM; Schönegger, A; Marcellus, R; Bilban, M; Bock, C; Brown, PJ; Zuber, J; Bennett, KL; Al-Awar, R; Delwel, R; Nerlov, C; Arrowsmith, CH; Superti-Furga, G

Titel: Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.

Quelle: Nat Chem Biol. 2015; 11(8):571-578



Autor/innen der Vetmeduni Vienna:

Grebien Florian

Diese Publikation wurde nicht im Namen der Vetmeduni Vienna erstellt und ist deshalb ausschließlich der persönlichen Publikationsliste des/der Autors/Autorin zugeordnet!


Abstract:
The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

Keywords Pubmed: Amino Acid Sequence
Animals
Antineoplastic Agents/pharmacology*
Biphenyl Compounds/pharmacology*
CCAAT-Enhancer-Binding Proteins/genetics
CCAAT-Enhancer-Binding Proteins/metabolism
Cell Differentiation/drug effects
Cell Proliferation/drug effects
Dihydropyridines/pharmacology*
Gene Expression Regulation, Neoplastic*
Histone-Lysine N-Methyltransferase/antagonists & inhibitors*
Histone-Lysine N-Methyltransferase/genetics
Histone-Lysine N-Methyltransferase/metabolism
Histones/genetics
Histones/metabolism
Humans
Leukemia, Myeloid, Acute/genetics
Leukemia, Myeloid, Acute/metabolism*
Leukemia, Myeloid, Acute/pathology
Mice
Molecular Docking Simulation
Molecular Sequence Data
Molecular Targeted Therapy
Mutation
Myeloid-Lymphoid Leukemia Protein/antagonists & inhibitors*
Myeloid-Lymphoid Leukemia Protein/genetics
Myeloid-Lymphoid Leukemia Protein/metabolism
Protein Binding
Protein Isoforms/genetics
Protein Isoforms/metabolism
Protein Structure, Tertiary
Signal Transduction
Small Molecule Libraries/pharmacology*
Tumor Cells, Cultured


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