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

Nature Communications
Anna SkuchaFlorian Grebien

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.

References

Aug 5, 1997·Proceedings of the National Academy of Sciences of the United States of America·O M SobuloN J Zeleznik-Le
Oct 3, 2003·Cancer Cell·Mary Ellen MartinJay L Hess
Nov 5, 2004·Nature·Yentram HuyenThanos D Halazonetis
Aug 1, 2006·Nature Structural & Molecular Biology·Yali DouRobert G Roeder
Mar 16, 2007·Nature Reviews. Cancer·Felix MitelmanFredrik Mertens
Sep 25, 2007·Nature Cell Biology·Ngai CheungChi Wai Eric So
Jul 5, 2008·Cancer Cell·Akihiko Yokoyama, Michael L Cleary
Nov 4, 2009·Nucleic Acids Research·Andreas RueppH-Werner Mewes
Dec 17, 2009·Nature Structural & Molecular Biology·Tomasz CierpickiJohn H Bushweller
Jul 12, 2011·Cancer Cell·Kathrin M BerntScott A Armstrong
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Debabrata BiswasRobert G Roeder
Feb 4, 2012·Nature Protocols·Lukas E DowScott W Lowe
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Jan 5, 2013·Science·Le CongFeng Zhang
Mar 20, 2013·Molecular and Cellular Biology·Rick van NulandH T Marc Timmers
May 1, 2013·Leukemia·C MeyerR Marschalek
Jun 27, 2013·Blood·Scott R DaigleRoy M Pollock
Aug 14, 2013·Journal of Proteome Research·Roberto GiambrunoKeiryn L Bennett
Dec 18, 2013·Cell Reports·Christof FellmannJohannes Zuber
Dec 25, 2013·The Journal of Experimental Medicine·Ewa OhlssonBo Torben Porse
Jan 28, 2014·Nucleic Acids Research·Hiroshi OkudaAkihiko Yokoyama
Apr 8, 2014·Journal of Proteomics·Jacques ColingeGiulio Superti-Furga
Aug 1, 2014·Nature·Margarida A SantosAndré Nussenzweig
Sep 28, 2014·Bioinformatics·Simon AndersWolfgang Huber

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Citations

Oct 26, 2018·Nucleic Acids Research·Madalina GiurgiuAndreas Ruepp
May 31, 2019·Cellular and Molecular Life Sciences : CMLS·Jie LiGang Greg Wang
Aug 24, 2019·Nature Communications·Silvija Bilokapic, Mario Halic
Dec 6, 2019·British Journal of Haematology·Luke JonesJonathan Bond
Oct 5, 2019·Nature Structural & Molecular Biology·Dylan Husmann, Or Gozani
Dec 13, 2019·Nature·Laura MacPhersonMark A Dawson
Apr 23, 2020·Cellular and Molecular Life Sciences : CMLS·Zhenhua Yang, Hao Jiang
Feb 6, 2020·Cell & Bioscience·Zhongxing SunDong Fang
Sep 27, 2018·Molecular & Cellular Oncology·Anna SkuchaFlorian Grebien
Nov 30, 2018·Expert Review of Proteomics·Dylan M MarchioneJohn Wojcik
Mar 2, 2019·International Journal of Molecular Sciences·Anna SkuchaFlorian Grebien
Jan 21, 2021·Nature Reviews. Drug Discovery·Kamakoti P BhatOr Gozani
Jan 23, 2021·Nature Structural & Molecular Biology·Stefan Terlecki-ZaniewiczFlorian Grebien
Mar 10, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Simone Aparecida de Bessa GarciaRenata Freitas
Jun 14, 2020·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Nok-Hei Mickey Wong, Chi Wai Eric So
May 29, 2021·Nature Communications·Dávid BajuszGyörgy M Keserű

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Datasets Mentioned

BETA
PXD009338
GSE110521

Methods Mentioned

BETA
nuclear translocation
affinity purification
flow cytometry
affinity-purification
co-immunoprecipitation
PCR
affinity purifications
pulldowns
immunoprecipitation
ChIP-seq

Software Mentioned

PRINSEQ
CORUM
Phenyx
Gephi
Illumina2bam
Cytoscape
BWA
pheatmap
FlowJo
FastQC

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