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Nat Commun. 2018 May 18;9(1):1983. doi: 10.1038/s41467-018-04329-y.

MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria.
2
Ludwig Boltzmann Institute for Cancer Research, Vienna, 1090, Austria.
3
Research Institute of Molecular Pathology, Vienna, 1030, Austria.
4
Cold Spring Harbor Larboratory, Cold Spring Harbor, 11724, NY, USA.
5
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Second Department of Pediatrics, Semmelweis University, Budapest, 1094, Hungary.
6
Department of Internal Medicine I. Division of Hematology and Hemostaseology, Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, 1090, Austria.
7
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, 1090, Austria.
8
Ludwig Boltzmann Institute for Cancer Research, Vienna, 1090, Austria. florian.grebien@vetmeduni.ac.at.
9
Institute for Medical Biochemistry, University of Veterinary Medicine, Vienna, 1210, Austria. florian.grebien@vetmeduni.ac.at.

Abstract

MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins. Functional investigation of 128 conserved MLL-fusion-interactors identifies a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss causes growth arrest and differentiation of AML cells, and leads to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 is required to maintain high H3K79 di-methylation and MLL-AF9-binding to critical target genes, such as Hoxa9. SETD2 loss synergizes with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation, and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.

PMID:
29777171
PMCID:
PMC5959866
DOI:
10.1038/s41467-018-04329-y
[Indexed for MEDLINE]
Free PMC Article

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