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Ari Melnick

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https://www.readbyqxmd.com/read/27881822/lowered-h3k27me3-and-dna-hypomethylation-define-poorly-prognostic-pediatric-posterior-fossa-ependymomas
#1
Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant U Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley S Margol, Pooja Panwalkar, Abhijit Parolia, Melike Pekmezci, Richard C McEachin, Marcin Cieslik, Benita Tamrazi, Benjamin A Garcia, Gaspare La Rocca, Mariarita Santi, Peter W Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B Thompson, Arul M Chinnaiyan, Alexander R Judkins, Sriram Venneti
Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas...
November 23, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27881582/the-expanding-role-of-the-bcl6-oncoprotein-as-a-cancer-therapeutic-target
#2
Mariano G Cardenas, Erin Oswald, Wenbo Yu, Fengtian Xue, Alexander D MacKerell, Ari M Melnick
BCL6 was initially discovered as an oncogene in B-cell lymphomas, where it drives the malignant phenotype by repressing proliferation and DNA damage checkpoints and blocking B-cell terminal differentiation. BCL6 mediates its effects by binding to hundreds of target genes, and then repressing these genes by recruiting several different chromatin modifying corepressor complexes. Structural characterization of BCL6-corepressor complexes suggested that BCL6 might be a druggable target. Accordingly a number of compounds have been designed to bind to BCL6 and block corepressor recruitment...
November 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27791114/roles-for-small-noncoding-rnas-in-silencing-of-retrotransposons-in-the-mammalian-brain
#3
Sayan Nandi, Dhruva Chandramohan, Luana Fioriti, Ari M Melnick, Jean M Hébert, Christopher E Mason, Priyamvada Rajasethupathy, Eric R Kandel
Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons of Aplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27733359/crebbp-inactivation-promotes-the-development-of-hdac3-dependent-lymphomas
#4
Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia-Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S Doane, Xabier Agirre Ena, Matt Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W Scott, Kristy R Stengel, Janice E Kranz, Edward Holson, Sneh Sharma, James W Young, Chi-Shuen Chu, Robert G Roeder, Rita Shaknovich, Scott W Hiebert, Randy D Gascoyne, Wayne Tam, Olivier Elemento, Hans-Guido Wendel, Ari M Melnick
Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates development of germinal center derived lymphomas in mice. In both human and murine lymphomas CREBBP loss of function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses including class II MHC. Mechanistically, CREBBP regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we find bind extensively to MHC class II loci...
October 12, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27706135/the-epichaperome-is-an-integrated-chaperome-network-that-facilitates-tumour-survival
#5
Anna Rodina, Tai Wang, Pengrong Yan, Erica DaGama Gomes, Mark P S Dunphy, Nagavarakishore Pillarsetty, John Koren, John F Gerecitano, Tony Taldone, Hongliang Zong, Eloisi Caldas-Lopes, Mary Alpaugh, Adriana Corben, Matthew Riolo, Brad Beattie, Christina Pressl, Radu I Peter, Chao Xu, Robert Trondl, Hardik J Patel, Fumiko Shimizu, Alexander Bolaender, Chenghua Yang, Palak Panchal, Mohammad F Farooq, Sarah Kishinevsky, Shanu Modi, Oscar Lin, Feixia Chu, Sujata Patil, Hediye Erdjument-Bromage, Pat Zanzonico, Clifford Hudis, Lorenz Studer, Gail J Roboz, Ethel Cesarman, Leandro Cerchietti, Ross Levine, Ari Melnick, Steven M Larson, Jason S Lewis, Monica L Guzman, Gabriela Chiosis
Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis...
October 5, 2016: Nature
https://www.readbyqxmd.com/read/27637145/multi-tiered-reorganization-of-the-genome-during-b-cell-affinity-maturation-anchored-by-a-germinal-center-specific-locus-control-region
#6
Karen L Bunting, T David Soong, Rajat Singh, Yanwen Jiang, Wendy Béguelin, David W Poloway, Brandon L Swed, Katerina Hatzi, William Reisacher, Matt Teater, Olivier Elemento, Ari M Melnick
During the humoral immune response, B cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Using genome-wide chromosomal conformation capture (Hi-C), we found that GC B cells undergo massive reorganization of the genomic architecture that encodes the GC B cell transcriptome. Coordinate expression of genes that specify the GC B cell phenotype-most prominently BCL6-was achieved through a multilayered chromatin reorganization process involving (1) increased promoter connectivity, (2) formation of enhancer networks, (3) 5' to 3' gene looping, and (4) merging of gene neighborhoods that share active epigenetic marks...
September 20, 2016: Immunity
https://www.readbyqxmd.com/read/27505670/ezh2-and-bcl6-cooperate-to-assemble-cbx8-bcor-complex-to-repress-bivalent-promoters-mediate-germinal-center-formation-and-lymphomagenesis
#7
Wendy Béguelin, Matt Teater, Micah D Gearhart, María Teresa Calvo Fernández, Rebecca L Goldstein, Mariano G Cárdenas, Katerina Hatzi, Monica Rosen, Hao Shen, Connie M Corcoran, Michelle Y Hamline, Randy D Gascoyne, Ross L Levine, Omar Abdel-Wahab, Jonathan D Licht, Rita Shaknovich, Olivier Elemento, Vivian J Bardwell, Ari M Melnick
The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications...
August 8, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27503926/sirt2-deacetylates-and-inhibits-the-peroxidase-activity-of-peroxiredoxin-1-to-sensitize-breast-cancer-cells-to-oxidant-stress-inducing-agents
#8
Warren Fiskus, Veena Coothankandaswamy, Jianguang Chen, Hongwei Ma, Kyungsoo Ha, Dyana T Saenz, Stephanie S Krieger, Christopher P Mill, Baohua Sun, Peng Huang, Jeffrey S Mumm, Ari M Melnick, Kapil N Bhalla
SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27477909/a-highly-sensitive-and-robust-method-for-genome-wide-5hmc-profiling-of-rare-cell-populations
#9
Dali Han, Xingyu Lu, Alan H Shih, Ji Nie, Qiancheng You, Meng Michelle Xu, Ari M Melnick, Ross L Levine, Chuan He
We present a highly sensitive and selective chemical labeling and capture approach for genome-wide profiling of 5-hydroxylmethylcytosine (5hmC) using DNA isolated from ∼1,000 cells (nano-hmC-Seal). Using this technology, we assessed 5hmC occupancy and dynamics across different stages of hematopoietic differentiation. Nano-hmC-Seal profiling of purified Tet2-mutant acute myeloid leukemia (AML) murine stem cells allowed us to identify leukemia-specific, differentially hydroxymethylated regions that harbor known and candidate disease-specific target genes with differential 5hmC peaks compared to normal stem cells...
August 18, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27446991/a-clinical-measure-of-dna-methylation-predicts-outcome-in-de-novo-acute-myeloid-leukemia
#10
Marlise R Luskin, Phyllis A Gimotty, Catherine Smith, Alison W Loren, Maria E Figueroa, Jenna Harrison, Zhuoxin Sun, Martin S Tallman, Elisabeth M Paietta, Mark R Litzow, Ari M Melnick, Ross L Levine, Hugo F Fernandez, Selina M Luger, Martin Carroll, Stephen R Master, Gerald B W Wertheim
BACKGROUND: Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML. METHODS: We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy...
June 16, 2016: JCI Insight
https://www.readbyqxmd.com/read/27431380/mutant-idh-a-targetable-driver-of-leukemic-phenotypes-linking-metabolism-epigenetics-and-transcriptional-regulation
#11
Francine E Garrett-Bakelman, Ari M Melnick
Aberrant epigenomic programming is a hallmark of acute myeloid leukemia. This is partially due to somatic mutations that perturb cytosine methylation, histone post-translational modifications and transcription factors. Remarkably, mutations in the IDH1 and IDH2 genes perturb the epigenome through all three of these mechanisms. Mutant IDH enzymes produce high levels of the oncometabolite (R)-2-hydroxyglutarate that competitively inhibits dioxygenase enzymes that modify methylcytosine to hydroxymethylcytosine and histone tail methylation...
July 2016: Epigenomics
https://www.readbyqxmd.com/read/27322744/distinct-evolution-and-dynamics-of-epigenetic-and-genetic-heterogeneity-in-acute-myeloid-leukemia
#12
Sheng Li, Francine E Garrett-Bakelman, Stephen S Chung, Mathijs A Sanders, Todd Hricik, Franck Rapaport, Jay Patel, Richard Dillon, Priyanka Vijay, Anna L Brown, Alexander E Perl, Joy Cannon, Lars Bullinger, Selina Luger, Michael Becker, Ian D Lewis, Luen Bik To, Ruud Delwel, Bob Löwenberg, Hartmut Döhner, Konstanze Döhner, Monica L Guzman, Duane C Hassane, Gail J Roboz, David Grimwade, Peter J M Valk, Richard J D'Andrea, Martin Carroll, Christopher Y Park, Donna Neuberg, Ross Levine, Ari M Melnick, Christopher E Mason
Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression...
July 2016: Nature Medicine
https://www.readbyqxmd.com/read/27297662/homeobox-nkx2-3-promotes-marginal-zone-lymphomagenesis-by-activating-b-cell-receptor-signalling-and-shaping-lymphocyte-dynamics
#13
Eloy F Robles, Maria Mena-Varas, Laura Barrio, Sara V Merino-Cortes, Péter Balogh, Ming-Qing Du, Takashi Akasaka, Anton Parker, Sergio Roa, Carlos Panizo, Idoia Martin-Guerrero, Reiner Siebert, Victor Segura, Xabier Agirre, Laura Macri-Pellizeri, Beatriz Aldaz, Amaia Vilas-Zornoza, Shaowei Zhang, Sarah Moody, Maria Jose Calasanz, Thomas Tousseyn, Cyril Broccardo, Pierre Brousset, Elena Campos-Sanchez, Cesar Cobaleda, Isidro Sanchez-Garcia, Jose Luis Fernandez-Luna, Ricardo Garcia-Muñoz, Esther Pena, Beatriz Bellosillo, Antonio Salar, Maria Joao Baptista, Jesús Maria Hernandez-Rivas, Marcos Gonzalez, Maria Jose Terol, Joan Climent, Antonio Ferrandez, Xavier Sagaert, Ari M Melnick, Felipe Prosper, David G Oscier, Yolanda R Carrasco, Martin J S Dyer, Jose A Martinez-Climent
NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas...
June 14, 2016: Nature Communications
https://www.readbyqxmd.com/read/27270773/reply-to-uveal-melanoma-cells-are-resistant-to-ezh2-inhibition-regardless-of-bap1-status
#14
Lindsay M LaFave, Wendy Béguelin, Richard Koche, Matt Teater, Barbara Spitzer, Alan Chramiec, Efthymia Papalexi, Matthew D Keller, Todd Hricik, Katerina Konstantinoff, Jean-Baptiste Micol, Benjamin Durham, Sarah K Knutson, John E Campbell, Gil Blum, Xinxu Shi, Emma H Doud, Andrei V Krivtsov, Young Rock Chung, Inna Khodos, Elisa de Stanchina, Ouathek Ouerfelli, Prasad S Adusumilli, Paul M Thomas, Neil L Kelleher, Minkui Luo, Heike Keilhack, Omar Abdel-Wahab, Ari Melnick, Scott A Armstrong, Ross L Levine
No abstract text is available yet for this article.
June 7, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27162099/genetic-and-epigenetic-heterogeneity-in-acute-myeloid-leukemia
#15
REVIEW
Sheng Li, Christopher E Mason, Ari Melnick
Genetic and epigenetic heterogeneity is emerging as a fundamental property of human cancers. Reflecting the genesis of tumors as an evolutionary process driven by clonal selection. The complexity of clonal architecture has been known for many years in the setting of acute myeloid leukemia (AML), based on karyotyping studies. However the true complexity of AMLs is only now being understood thanks to in depth genome sequencing studies in humans, which reveal that heterogeneity is a multilayered and involves not only the genome but also the epigenome...
February 2016: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/27127301/pathogenic-role-of-b-cell-receptor-signaling-and-canonical-nf-%C3%AE%C2%BAb-activation-in-mantle-cell-lymphoma
#16
Nakhle S Saba, Delong Liu, Sarah E M Herman, Chingiz Underbayev, Xin Tian, David Behrend, Marc A Weniger, Martin Skarzynski, Jennifer Gyamfi, Lorena Fontan, Ari Melnick, Cliona Grant, Mark Roschewski, Alba Navarro, Sílvia Beà, Stefania Pittaluga, Kieron Dunleavy, Wyndham H Wilson, Adrian Wiestner
To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown...
July 7, 2016: Blood
https://www.readbyqxmd.com/read/27055146/the-many-layers-of-epigenetic-dysfunction-in-b-cell-lymphomas
#17
Yanwen Jiang, Pilar M Dominguez, Ari M Melnick
PURPOSE OF REVIEW: Perturbation of the epigenome is emerging as a central driving force in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. The purpose of this review is to explain how alteration of different layers of the epigenome contributes to the biology and clinical features of these tumors. RECENT FINDINGS: Key new findings implicate DNA methylation heterogeneity as a core feature of DLBCL. Epigenetic diversity is linked to unfavorable clinical outcomes, clonal selection at relapse, and is driven at least in part because of the actions of activation-induced cytosine deaminase, which is a unique feature of B-cell lymphomas...
July 2016: Current Opinion in Hematology
https://www.readbyqxmd.com/read/27016502/dnmt3a-haploinsufficiency-transforms-flt3itd-myeloproliferative-disease-into-a-rapid-spontaneous-and-fully-penetrant-acute-myeloid-leukemia
#18
Sara E Meyer, Tingting Qin, David E Muench, Kohei Masuda, Meenakshi Venkatasubramanian, Emily Orr, Lauren Suarez, Steven D Gore, Ruud Delwel, Elisabeth Paietta, Martin S Tallman, Hugo Fernandez, Ari Melnick, Michelle M Le Beau, Scott Kogan, Nathan Salomonis, Maria E Figueroa, H Leighton Grimes
UNLABELLED: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency...
May 2016: Cancer Discovery
https://www.readbyqxmd.com/read/26974310/pten-opposes-negative-selection-and-enables-oncogenic-transformation-of-pre-b-cells
#19
Seyedmehdi Shojaee, Lai N Chan, Maike Buchner, Valeria Cazzaniga, Kadriye Nehir Cosgun, Huimin Geng, Yi Hua Qiu, Marcus Dühren von Minden, Thomas Ernst, Andreas Hochhaus, Giovanni Cazzaniga, Ari Melnick, Steven M Kornblau, Thomas G Graeber, Hong Wu, Hassan Jumaa, Markus Müschen
Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia...
April 2016: Nature Medicine
https://www.readbyqxmd.com/read/26958840/corrigendum-signalling-thresholds-and-negative-b-cell-selection-in-acute-lymphoblastic-leukaemia
#20
Zhengshan Chen, Seyedmehdi Shojaee, Maike Buchner, Huimin Geng, Jae Woong Lee, Lars Klemm, Björn Titz, Thomas G Graeber, Eugene Park, Ying Xim Tan, Anne Satterthwaite, Elisabeth Paietta, Stephen P Hunger, Cheryl L Willman, Ari Melnick, Mignon L Loh, Jae U Jung, John E Coligan, Silvia Bolland, Tak W Mak, Andre Limnander, Hassan Jumaa, Michael Reth, Arthur Weiss, Clifford A Lowell, Markus Müschen
No abstract text is available yet for this article.
June 2, 2016: Nature
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