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Ari Melnick

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https://www.readbyqxmd.com/read/29502954/ory-1001-a-potent-and-selective-covalent-kdm1a-inhibitor-for-the-treatment-of-acute-leukemia
#1
Tamara Maes, Cristina Mascaró, Iñigo Tirapu, Angels Estiarte, Filippo Ciceri, Serena Lunardi, Nathalie Guibourt, Alvaro Perdones, Michele M P Lufino, Tim C P Somervaille, Dan H Wiseman, Cihangir Duy, Ari Melnick, Christophe Willekens, Alberto Ortega, Marc Martinell, Nuria Valls, Guido Kurz, Matthew Fyfe, Julio Cesar Castro-Palomino, Carlos Buesa
The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia...
March 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29431698/mef2c-phosphorylation-is-required-for-chemotherapy-resistance-in-acute-myeloid-leukemia
#2
Fiona C Brown, Eric Still, Richard P Koche, Christina Y Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O'Donnell, Barbara Spitzer, Crystal Stutzke, Vincent-Philippe Lavallée, Josée Hébert, Andrei V Krivtsov, Ari Melnick, Elisabeth M Paietta, Martin S Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A Marto, Scott A Armstrong, Alex Kentsis
In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9 MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells...
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29395070/engineering-of-a-histone-recognition-domain-in-dnmt3a-alters-the-epigenetic-landscape-and-phenotypic-features-of-mouse-escs
#3
Kyung-Min Noh, Haibo Wang, Hyunjae R Kim, Wendy Wenderski, Fang Fang, Charles H Li, Scott Dewell, Stephen H Hughes, Ari M Melnick, Dinshaw J Patel, Haitao Li, C David Allis
No abstract text is available yet for this article.
February 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29335468/aicda-drives-epigenetic-heterogeneity-and-accelerates-germinal-center-derived-lymphomagenesis
#4
Matt Teater, Pilar M Dominguez, David Redmond, Zhengming Chen, Daisuke Ennishi, David W Scott, Luisa Cimmino, Paola Ghione, Jayanta Chaudhuri, Randy D Gascoyne, Iannis Aifantis, Giorgio Inghirami, Olivier Elemento, Ari Melnick, Rita Shaknovich
Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29275866/cooperative-epigenetic-remodeling-by-tet2-loss-and-nras-mutation-drives-myeloid-transformation-and-mek-inhibitor-sensitivity
#5
Hiroyoshi Kunimoto, Cem Meydan, Abbas Nazir, Justin Whitfield, Kaitlyn Shank, Franck Rapaport, Rebecca Maher, Elodie Pronier, Sara C Meyer, Francine E Garrett-Bakelman, Martin Tallman, Ari Melnick, Ross L Levine, Alan H Shih
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing...
January 8, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29026085/ezh2-enables-germinal-centre-formation-through-epigenetic-silencing-of-cdkn1a-and-an-rb-e2f1-feedback-loop
#6
Wendy Béguelin, Martín A Rivas, María T Calvo Fernández, Matt Teater, Alberto Purwada, David Redmond, Hao Shen, Matt F Challman, Olivier Elemento, Ankur Singh, Ari M Melnick
The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1 ). Deletion of Cdkn1a rescues the GC reaction in Ezh2-/- mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a-/- Ezh2-/- mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28993409/malt1-inhibition-is-efficacious-in-both-na%C3%A3-ve-and-ibrutinib-resistant-chronic-lymphocytic-leukemia
#7
Nakhle S Saba, Deanna H Wong, Georges Tanios, Jessica R Iyer, Patricia Lobelle-Rich, Eman L Dadashian, Delong Liu, Lorena Fontan, Erik K Flemington, Cydney M Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E M Herman
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2 , a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28985559/untangling-the-web-of-lymphoma-somatic-mutations
#8
COMMENT
Matt Teater, Ari Melnick
In this issue of Cell, Reddy et al. report integrative genetic characterization of diffuse large B cell lymphomas (DLBCL), including large-scale exome capture, transcriptomes, CRISPR screens, and integrative clinical biomarker studies. This provides the first comprehensive overview of DLBCL biology and the basis for future precision medicine approaches to this disease.
October 5, 2017: Cell
https://www.readbyqxmd.com/read/28920958/the-n-6-methyladenosine-m-6-a-forming-enzyme-mettl3-controls-myeloid-differentiation-of-normal-hematopoietic-and-leukemia-cells
#9
Ly P Vu, Brian F Pickering, Yuanming Cheng, Sara Zaccara, Diu Nguyen, Gerard Minuesa, Timothy Chou, Arthur Chow, Yogesh Saletore, Matthew MacKay, Jessica Schulman, Christopher Famulare, Minal Patel, Virginia M Klimek, Francine E Garrett-Bakelman, Ari Melnick, Martin Carroll, Christopher E Mason, Samie R Jaffrey, Michael G Kharas
N6 -methyladenosine (m6 A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6 A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6 A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth...
November 2017: Nature Medicine
https://www.readbyqxmd.com/read/28659443/genetic-and-epigenetic-inactivation-of-sestrin1-controls-mtorc1-and-response-to-ezh2-inhibition-in-follicular-lymphoma
#10
Elisa Oricchio, Natalya Katanayeva, Maria Christine Donaldson, Stephanie Sungalee, Joyce P Pasion, Wendy Béguelin, Elena Battistello, Viraj R Sanghvi, Man Jiang, Yanwen Jiang, Matt Teater, Anita Parmigiani, Andrei V Budanov, Fong Chun Chan, Sohrab P Shah, Robert Kridel, Ari M Melnick, Giovanni Ciriello, Hans-Guido Wendel
Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2 Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation ( EZH2 Y641X ). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress...
June 28, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28590361/editorial-introductions
#11
Hal E Broxmeyer, Ari Melnick
No abstract text is available yet for this article.
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28436985/functional-screen-of-msi2-interactors-identifies-an-essential-role-for-syncrip-in-myeloid-leukemia-stem-cells
#12
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...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28408400/epigenetic-identity-in-aml-depends-on-disruption-of-nonpromoter-regulatory-elements-and-is-affected-by-antagonistic-effects-of-mutations-in-epigenetic-modifiers
#13
Jacob L Glass, Duane Hassane, Bas J Wouters, Hiroyoshi Kunimoto, Roberto Avellino, Francine E Garrett-Bakelman, Olga A Guryanova, Robert Bowman, Shira Redlich, Andrew M Intlekofer, Cem Meydan, Tingting Qin, Mame Fall, Alicia Alonso, Monica L Guzman, Peter J M Valk, Craig B Thompson, Ross Levine, Olivier Elemento, Ruud Delwel, Ari Melnick, Maria E Figueroa
We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions...
August 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28378425/follicular-lymphoma-state-of-the-art-icml-workshop-in-lugano-2015
#14
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...
December 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
#15
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...
May 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28130226/effective-combination-therapies-for-b-cell-lymphoma-predicted-by-a-virtual-disease-model
#16
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
#17
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
#18
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
#19
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
#20
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
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