Journal ArticleDOI
Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms
Ayana Kon,Lee Yung Shih,Masashi Minamino,Masashi Sanada,Masashi Sanada,Yuichi Shiraishi,Yasunobu Nagata,Kenichi Yoshida,Yusuke Okuno,Masashige Bando,Ryuichiro Nakato,Shumpei Ishikawa,Shumpei Ishikawa,Aiko Sato-Otsubo,Genta Nagae,Aiko Nishimoto,Claudia Haferlach,Daniel Nowak,Yusuke Sato,Tamara Alpermann,Masao Nagasaki,Teppei Shimamura,Hiroko Tanaka,Kenichi Chiba,Ryo Yamamoto,Tomoyuki Yamaguchi,Makoto Otsu,Naoshi Obara,Mamiko Sakata-Yanagimoto,Tsuyoshi Nakamaki,Ken Ishiyama,Florian Nolte,Wolf-Karsten Hofmann,Shuichi Miyawaki,Shigeru Chiba,Hiraku Mori,Hiromitsu Nakauchi,H. Phillip Koeffler,H. Phillip Koeffler,Hiroyuki Aburatani,Torsten Haferlach,Katsuhiko Shirahige,Satoru Miyano,Seishi Ogawa,Seishi Ogawa +44 more
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TLDR
A role for compromised cohesin functions in myeloid leukemogenesis is suggested by the growth of leukemic cell lines harboring a mutation in RAD21 or having severely reduced expression of RAD21 and STAG2 being suppressed by forced expression of wild-type RAD21 (Kasumi-1 cells and MOLM-13 cells).Abstract:
Cohesin is a multimeric protein complex that is involved in the cohesion of sister chromatids, post-replicative DNA repair and transcriptional regulation. Here we report recurrent mutations and deletions involving multiple components of the cohesin complex, including STAG2, RAD21, SMC1A and SMC3, in different myeloid neoplasms. These mutations and deletions were mostly mutually exclusive and occurred in 12.1% (19/157) of acute myeloid leukemia, 8.0% (18/224) of myelodysplastic syndromes, 10.2% (9/88) of chronic myelomonocytic leukemia, 6.3% (4/64) of chronic myelogenous leukemia and 1.3% (1/77) of classical myeloproliferative neoplasms. Cohesin-mutated leukemic cells showed reduced amounts of chromatin-bound cohesin components, suggesting a substantial loss of cohesin binding sites on chromatin. The growth of leukemic cell lines harboring a mutation in RAD21 (Kasumi-1 cells) or having severely reduced expression of RAD21 and STAG2 (MOLM-13 cells) was suppressed by forced expression of wild-type RAD21 and wild-type RAD21 and STAG2, respectively. These findings suggest a role for compromised cohesin functions in myeloid leukemogenesis.read more
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Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.
Michele Ceccarelli,Floris P. Barthel,Tathiane M. Malta,Thais S. Sabedot,Sofie R. Salama,Bradley A. Murray,Olena Morozova,Yulia Newton,Amie Radenbaugh,Stefano Maria Pagnotta,Samreen Anjum,Jiguang Wang,Ganiraju C. Manyam,Pietro Zoppoli,Shiyun Ling,Arjun A. Rao,Mia Grifford,Andrew D. Cherniack,Hailei Zhang,Laila M. Poisson,Carlos Gilberto Carlotti,Daniela Pretti da Cunha Tirapelli,Arvind Rao,Tom Mikkelsen,Ching C. Lau,W. K. Alfred Yung,Raul Rabadan,Jason T. Huse,Daniel J. Brat,Norman L. Lehman,Jill S. Barnholtz-Sloan,Siyuan Zheng,Kenneth R. Hess,Ganesh Rao,Matthew Meyerson,Rameen Beroukhim,Lee Cooper,Rehan Akbani,Margaret Wrensch,David Haussler,Kenneth Aldape,Peter W. Laird,David H. Gutmann,Houtan Noushmehr,Antonio Iavarone,Roel G.W. Verhaak +45 more
TL;DR: The complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas were defined from The Cancer Genome Atlas and molecular profiles were used to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease.
Journal ArticleDOI
Epigenetic plasticity and the hallmarks of cancer
TL;DR: It is proposed that chromatin and epigenetic aberrations have the potential to confer on cells the full range of oncogenic properties represented in the classic “hallmarks” depiction of cancer, and it is suggested that genetic, environmental, and metabolic factors can make chromatin aberrantly permissive or restrictive.
Journal ArticleDOI
Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes
Mark D.M. Leiserson,Fabio Vandin,Hsin-Ta Wu,Jason R. Dobson,Jonathan V. Eldridge,Jacob L. Thomas,Alexandra Papoutsaki,Younhun Kim,Beifang Niu,Michael D. McLellan,Michael S. Lawrence,Abel Gonzalez-Perez,David Tamborero,Yuwei Cheng,Gregory A. Ryslik,Nuria Lopez-Bigas,Gad Getz,Li Ding,Benjamin J. Raphael +18 more
TL;DR: A pan-cancer analysis of mutated networks in 3,281 samples from 12 cancer types from The Cancer Genome Atlas is performed using HotNet2, a new algorithm to find mutated subnetworks that overcomes the limitations of existing single-gene, pathway and network approaches.
Journal ArticleDOI
The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.
TL;DR: The molecular processes that lead to CHIP and further clonal evolution to MDS and sAML are discussed, and the ways in which these insights are shaping the clinical management of MDS are highlighted, including classification schemata, prognostic scoring systems and therapeutic approaches.
Journal ArticleDOI
Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
Franck Tirode,Didier Surdez,Xiaotu Ma,Matthew Parker,Marie-Cécile Le Deley,Armita Bahrami,Zhaojie Zhang,Eve Lapouble,Sandrine Grossetête-Lalami,Michael Rusch,Stéphanie Reynaud,Thomas Rio-Frio,Erin Hedlund,Gang Wu,Xiang Chen,Gaëlle Pierron,Odile Oberlin,Sakina Zaidi,Gordon Lemmon,Pankaj Gupta,Bhavin Vadodaria,John Easton,Marta Gut,Li Ding,Elaine R. Mardis,Richard K. Wilson,Sheila A. Shurtleff,Valérie Laurence,Jean Michon,Perrine Marec-Berard,Ivo Gut,James R. Downing,Michael A. Dyer,Michael A. Dyer,Jinghui Zhang,Olivier Delattre +35 more
TL;DR: Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies, and novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.
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