Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia
Jacob D. Jaffe,Yan Wang,Ho Man Chan,Jinghui Zhang,Robert Huether,Gregory V. Kryukov,Gregory V. Kryukov,Gregory V. Kryukov,Hyo-eun C. Bhang,Jordan E. Taylor,Min Hu,Nathan P. Englund,Feng Yan,Zhaofu Wang,E. Robert McDonald,Lei Wei,Jing Ma,John Easton,Zhengtian Yu,Rosalie deBeaumount,Veronica Gibaja,Kavitha Venkatesan,Robert Schlegel,William R. Sellers,Nicholas Keen,Jun Liu,Giordano Caponigro,Jordi Barretina,Vesselina G. Cooke,Charles G. Mullighan,Steven A. Carr,James R. Downing,Levi A. Garraway,Levi A. Garraway,Frank Stegmeier +34 more
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TLDR
In this article, a high-information-content mass spectrometry approach was developed to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures.Abstract:
Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration in 14% of t(12;21) ETV6-RUNX1–containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.read more
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Journal ArticleDOI
Histone methyltransferase MMSET promotes AID-mediated DNA breaks at the donor switch region during class switch recombination.
Hai Vu Nguyen,Hai Vu Nguyen,Junchao Dong,Junchao Dong,Rohit A. Panchakshari,Rohit A. Panchakshari,Vipul Kumar,Vipul Kumar,Frederick W. Alt,Frederick W. Alt,Jean-Christophe Bories +10 more
TL;DR: Deletion of multiple myeloma SET domain (MMSET), a histone methyltransferase that is deregulated in various lymphoid malignancies, reduces DNA cleavage at the upstream Ig gene region without affecting joining of DSBs by the C-NHEJ pathway, suggesting an important role for the HMT MMSET in promoting AID-mediated DNA breaks during CSR.
Journal ArticleDOI
Defining the NSD2 interactome: PARP1 PARylation reduces NSD2 histone methyltransferase activity and impedes chromatin binding
Xiaoxiao Huang,Xiaoxiao Huang,Richard D. LeDuc,Luca Fornelli,Alissa J. Schunter,Richard L. Bennett,Neil L. Kelleher,Jonathan D. Licht +7 more
TL;DR: Clear evidence of cross-talk between PARylation and histone methylation is provided and offers new directions to characterize NSD2 function in DNA damage response, transcriptional regulation, and other pathways.
Journal ArticleDOI
Mass spectrometry-based characterization of histones in clinical samples: applications, progresses, and challenges
TL;DR: In this article, mass spectrometry (MS) has been used for the analysis of epigenetic marks in cell lines and animal tissue and, thanks to recent technological advances, is now ready to be applied also to clinical samples.
Posted ContentDOI
Structural basis of the regulation of normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2
Ko Sato,Amarjeet Kumar,Keisuke Hamada,Chikako Okada,Asako Oguni,Ayumi Machiyama,Shun Sakuraba,Tomohiro Nishizawa,Osamu Nureki,Hidetoshi Kono,Kazuhiro Ogata,Toru Sengoku +11 more
TL;DR: Cryo-electron microscopy structure andKinetic analysis revealed two oncogenic mutations, E1099K and T1150A, to aberrantly activate NSD2 by increasing its catalytic turnover but not the nucleosome affinity, suggesting that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild type.
Journal ArticleDOI
Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
Željko Antić,Jiangyan Yu,Simon V. van Reijmersdal,Anke H.A. van Dijk,Linde Dekker,Wouter H. Segerink,Edwin Sonneveld,Marta Fiocco,Rob Pieters,Peter M. Hoogerbrugge,Frank N. van Leeuwen,Ad Geurts van Kessel,Esmé Waanders,Roland P. Kuiper +13 more
TL;DR: There is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment, and particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the sub clonal alterations were preserved at relapse.
References
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Journal ArticleDOI
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Jordi Barretina,Giordano Caponigro,Nicolas Stransky,Kavitha Venkatesan,Adam A. Margolin,Adam A. Margolin,Sungjoon Kim,Christine D. Wilson,Joseph Lehar,Gregory V. Kryukov,Dmitriy Sonkin,Anupama Reddy,Manway Liu,Lauren Murray,Michael F. Berger,Michael F. Berger,John Monahan,Paula Morais,Jodi Meltzer,Adam Korejwa,Judit Jané-Valbuena,Judit Jané-Valbuena,Felipa A. Mapa,Joseph Thibault,Eva Bric-Furlong,Pichai Raman,Aaron Shipway,Ingo H. Engels,Jill Cheng,Guoying K. Yu,Jianjun Yu,Peter Aspesi,Melanie de Silva,Kalpana Jagtap,Michael D. Jones,Li Wang,Charlie Hatton,Emanuele Palescandolo,Supriya Gupta,Scott Mahan,Carrie Sougnez,Robert C. Onofrio,Ted Liefeld,Laura E. MacConaill,Wendy Winckler,Michael R. Reich,Nanxin Li,Jill P. Mesirov,Stacey Gabriel,Gad Getz,Kristin G. Ardlie,Vivien W. Chan,Vic E. Myer,Barbara L. Weber,Jeffrey A. Porter,Markus Warmuth,Peter Finan,Jennifer L. Harris,Matthew Meyerson,Matthew Meyerson,Todd R. Golub,Michael Morrissey,William R. Sellers,Robert Schlegel,Levi A. Garraway,Levi A. Garraway +65 more
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Journal ArticleDOI
Skyline: an open source document editor for creating and analyzing targeted proteomics experiments
Brendan MacLean,Daniela M. Tomazela,Nicholas J. Shulman,Matthew C. Chambers,Gregory L. Finney,Barbara Frewen,Randall Kern,David L. Tabb,Daniel C. Liebler,Michael J. MacCoss +9 more
TL;DR: The Skyline user interface simplifies the development of mass spectrometer methods and the analysis of data from targeted proteomics experiments performed using selected reaction monitoring (SRM).
Journal ArticleDOI
The SWISS-MODEL Repository and associated resources
TL;DR: The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms.
Journal ArticleDOI
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
Charles G. Mullighan,Salil Goorha,Ina Radtke,Christopher B. Miller,Elaine Coustan-Smith,James Dalton,Kevin Girtman,Susan Mathew,Jing Ma,Stanley Pounds,Xiaoping Su,Ching-Hon Pui,Mary V. Relling,William E. Evans,Sheila A. Shurtleff,James R. Downing +15 more
TL;DR: It is suggested that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis and the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.
Journal ArticleDOI
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Michael T. McCabe,Heidi M. Ott,Gopinath Ganji,Susan Korenchuk,Christine Thompson,Glenn S. Van Aller,Yan Liu,Alan P. Graves,Anthony Della Pietra,Elsie Diaz,Louis V. LaFrance,Mellinger Mark,Celine Duquenne,Xinrong Tian,Ryan G. Kruger,Charles F. McHugh,Martin Brandt,William H. Miller,Dashyant Dhanak,Sharad K. Verma,Peter J. Tummino,Caretha L. Creasy +21 more
TL;DR: GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.
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