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Ari Melnick

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https://www.readbyqxmd.com/read/28436985/functional-screen-of-msi2-interactors-identifies-an-essential-role-for-syncrip-in-myeloid-leukemia-stem-cells
#1
Ly P Vu, Camila Prieto, Elianna M Amin, Sagar Chhangawala, Andrei Krivtsov, M Nieves Calvo-Vidal, Timothy Chou, Arthur Chow, Gerard Minuesa, Sun Mi Park, Trevor S Barlowe, James Taggart, Patrick Tivnan, Raquel P Deering, Lisa P Chu, Jeong-Ah Kwon, Cem Meydan, Javier Perales-Paton, Arora Arshi, Mithat Gönen, Christopher Famulare, Minal Patel, Elisabeth Paietta, Martin S Tallman, Yuheng Lu, Jacob Glass, Francine E Garret-Bakelman, Ari Melnick, Ross Levine, Fatima Al-Shahrour, Marcus Järås, Nir Hacohen, Alexia Hwang, Ralph Garippa, Christopher J Lengner, Scott A Armstrong, Leandro Cerchietti, Glenn S Cowley, David Root, John Doench, Christina Leslie, Benjamin L Ebert, Michael G Kharas
The identity of the RNA-binding proteins (RBPs) that govern cancer stem cells remains poorly characterized. The MSI2 RBP is a central regulator of translation of cancer stem cell programs. Through proteomic analysis of the MSI2-interacting RBP network and functional shRNA screening, we identified 24 genes required for in vivo leukemia. Syncrip was the most differentially required gene between normal and myeloid leukemia cells. SYNCRIP depletion increased apoptosis and differentiation while delaying leukemogenesis...
April 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28408400/epigenetic-identity-in-aml-depends-on-disruption-of-non-promoter-regulatory-elements-and-is-affected-by-antagonistic-effects-of-mutations-in-epigenetic-modifiers
#2
Jacob Glass, Duane C Hassane, Bas Wouters, Hiroyoshi Kunimoto, Roberto Avellino, Francine E Garrett-Bakelman, Olga A Guryanova, Robert Bowman, Shira Redlich, Andrew Intlekofer, Cem Meydan, Tingting Qin, Mame P Fall, Alicia Alonso, Monica L Guzman, Peter Jm Valk, Craig B Thompson, Ross L Levine, Olivier Elemento, Ruud Delwel, Ari Melnick, Maria E Figueroa
Aberrant DNA methylation of gene promoters is a hallmark of AML. To define more precisely how cytosine methylation is redistributed in AML, we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs...
April 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28378425/follicular-lymphoma-state-of-the-art-icml-workshop-in-lugano-2015
#3
REVIEW
Randy D Gascoyne, Bertrand Nadel, Laura Pasqualucci, Jude Fitzgibbon, Jacqueline E Payton, Ari Melnick, Oliver Weigert, Karin Tarte, John G Gribben, Jonathan W Friedberg, John F Seymour, Franco Cavalli, Emanuele Zucca
The 13th International Conference on Malignant Lymphoma held in Lugano in June 2015 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) with the aim of developing an up-to-date understanding of the biology of follicular lymphoma and the clinical implications of new findings in the field. Discussed topics included the mutational spectrum at diagnosis, the clinical correlates of genetic and epigenetic alterations, the mechanisms of clonal evolution and histological transformation, the cross talk between tumor cells and microenvironment, and the development of novel treatments...
April 4, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28193779/combination-targeted-therapy-to-disrupt-aberrant-oncogenic-signaling-and-reverse-epigenetic-dysfunction-in-idh2-and-tet2-mutant-acute-myeloid-leukemia
#4
Alan H Shih, Cem Meydan, Kaitlyn Shank, Francine E Garrett-Bakelman, Patrick S Ward, Andrew M Intlekofer, Abbas Nazir, Eytan M Stein, Kristina Knapp, Jacob Glass, Jeremy Travins, Kim Straley, Camelia Gliser, Christopher E Mason, Katharine Yen, Craig B Thompson, Ari Melnick, Ross L Levine
Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2 Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3(ITD) mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28130226/effective-combination-therapies-for-b-cell-lymphoma-predicted-by-a-virtual-disease-model
#5
Wei Du, Rebecca Goldstein, Yanwen Jiang, Omar Aly, Leandro Cerchietti, Ari Melnick, Olivier Elemento
The complexity of cancer signaling networks limits the efficacy of most single-agent treatments and brings about challenges in identifying effective combinatorial therapies. In this study, we used chronic active B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma as a model system to establish a computational framework to optimize combinatorial therapy in silico We constructed a detailed kinetic model of the BCR signaling network, which captured the known complex cross-talk between the NFκB, ERK, and AKT pathways and multiple feedback loops...
April 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28123069/cd99-is-a-therapeutic-target-on-disease-stem-cells-in-myeloid-malignancies
#6
Stephen S Chung, William S Eng, Wenhuo Hu, Mona Khalaj, Francine E Garrett-Bakelman, Montreh Tavakkoli, Ross L Levine, Martin Carroll, Virginia M Klimek, Ari M Melnick, Christopher Y Park
Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are initiated and sustained by self-renewing malignant stem cells; thus, eradication of AML and MDS stem cells is required for cure. We identified CD99 as a cell surface protein frequently overexpressed on AML and MDS stem cells. Expression of CD99 allows for prospective separation of leukemic stem cells (LSCs) from functionally normal hematopoietic stem cells in AML, and high CD99 expression on AML blasts enriches for functional LSCs as demonstrated by limiting dilution xenotransplant studies...
January 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28113009/dna-methylation-based-biomarkers
#7
Leandro Cerchietti, Ari Melnick
No abstract text is available yet for this article.
March 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28077417/aid-is-a-key-regulator-of-myeloid-erythroid-differentiation-and-dna-methylation-in-hematopoietic-stem-progenitor-cells
#8
Hiroyoshi Kunimoto, Anna Sophia McKenney, Cem Meydan, Kaitlyn Shank, Abbas Nazir, Franck Rapaport, Benjamin Durham, Francine E Garrett-Bakelman, Elodie Pronier, Alan H Shih, Ari Melnick, Jayanta Chaudhuri, Ross L Levine
Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated...
March 30, 2017: Blood
https://www.readbyqxmd.com/read/27986882/general-biomarker-recommendations-for-lymphoma
#9
Lisa Rimsza, Yuri Fedoriw, Louis M Staudt, Ari Melnick, Randy Gascoyne, Michael Crump, Lawrence Baizer, Kai Fu, Eric Hsi, John W C Chan, Lisa McShane, John P Leonard, Brad S Kahl, Richard F Little, Jonathan W Friedberg, Lale Kostakoglu
Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways...
December 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27881822/lowered-h3k27me3-and-dna-hypomethylation-define-poorly-prognostic-pediatric-posterior-fossa-ependymomas
#10
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
#11
REVIEW
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...
February 15, 2017: 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
#12
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
#13
Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia-Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S Doane, Xabier Agirre, 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 the development of germinal center (GC)-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 found to bind extensively to MHC class II loci...
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27706135/the-epichaperome-is-an-integrated-chaperome-network-that-facilitates-tumour-survival
#14
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 20, 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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