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

Anna Skucha, Jessica Ebner, Johannes Schmöllerl, Mareike Roth, Thomas Eder, Adrián César-Razquin, Alexey Stukalov, Sarah Vittori, Matthias Muhar, Bin Lu, Martin Aichinger, Julian Jude, André C. Müller, Balázs Győrffy, Christopher R. Vakoc, Peter Valent, Keiryn L. Bennett, Johannes Zuber, Giulio Superti-Furga and Florian Grebien ()
Additional contact information
Anna Skucha: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Jessica Ebner: Ludwig Boltzmann Institute for Cancer Research
Johannes Schmöllerl: Ludwig Boltzmann Institute for Cancer Research
Mareike Roth: Research Institute of Molecular Pathology
Thomas Eder: Ludwig Boltzmann Institute for Cancer Research
Adrián César-Razquin: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Alexey Stukalov: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Sarah Vittori: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Matthias Muhar: Research Institute of Molecular Pathology
Bin Lu: Cold Spring Harbor Larboratory
Martin Aichinger: Research Institute of Molecular Pathology
Julian Jude: Research Institute of Molecular Pathology
André C. Müller: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Balázs Győrffy: Semmelweis University
Christopher R. Vakoc: Cold Spring Harbor Larboratory
Peter Valent: Medical University of Vienna
Keiryn L. Bennett: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Johannes Zuber: Research Institute of Molecular Pathology
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Florian Grebien: Ludwig Boltzmann Institute for Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04329-y

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