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T-ALL epigenetics

Valerie Lee, Judy S Wang, Marianna L Zahurak, Elske C Gootjes, Henk M W Verheul, Rose M Parkinson, Zachary Kerner, Anup Sharma, Gary L Rosner, Ana De Jesus-Acosta, Daniel A Laheru, Dung T Le, Aram Oganesian, Ellen Lilly-Foreman, Thomas Brown, Peter A Jones, Stephen B Baylin, Nita Ahuja, Nilofer A Azad
PURPOSE: Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in mCRC patients previously treated with irinotecan. EXPERIMENTAL DESIGN: In this 3+3 dose-escalation study, mCRC patients previously exposed to irinotecan received guadecitabine days 1-5 of a 28 day cycle and irinotecan 125mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45mg/m2; DL -1: guadecitabine 30mg/m2; DL -1G: guadecitabine 30mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45mg/m2 with GFS...
August 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Marie-Pierre Belot, Anne-Laure Castell, Sophie Le Fur, Pierre Bougnères
IL2RA, a subunit of the high affinity receptor for interleukin-2 (IL2), plays a crucial role in immune homeostasis. Notably, IL2RA expression is induced in CD4+ T cells in response to various stimuli and is constitutive in regulatory T cells (Tregs). We selected for our study 18 CpGs located within cognate regulatory regions of the IL2RA locus and characterized their methylation in naive, regulatory, and memory CD4+ T cells. We found that 5/18 CpGs (notably CpG + 3502) show dynamic, active demethylation during the in vitro activation of naive CD4+ T cells...
August 10, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Przemyslaw Szafranski, Ewelina Kośmider, Qian Liu, Justyna A Karolak, Lauren Currie, Sandhya Parkash, Stephen G Kahler, Elizabeth Roeder, Rebecca O Littlejohn, Thomas S DeNapoli, Felix R Shardonofsky, Cody Henderson, George Powers, Virginie Poisson, Denis Bérubé, Luc Oligny, Jacques L Michaud, Sandra Janssens, Kris De Coen, Jo Van Dorpe, Annelies Dheedene, Matthew T Harting, Matthew D Weaver, Amir M Khan, Nina Tatevian, Jennifer Wambach, Kathleen A Gibbs, Edwina Popek, Anna Gambin, Paweł Stankiewicz
Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, lethal, neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue specific enhancer. Eighty five per cent of 45ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements...
August 6, 2018: Human Mutation
Changshan Wang, Motohiko Oshima, Daisuke Sato, Hirotaka Matsui, Sho Kubota, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Shuhei Koide, Jun Matsubayashi, Makiko Mochizuki-Kashio, Takako Nakano-Yokomizo, Jie Bai, Toshitaka Nagao, Akinori Kanai, Atsushi Iwama, Goro Sashida
Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL-like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs...
August 6, 2018: Journal of Clinical Investigation
David Bending, Masahiro Ono
Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor Foxp3. This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesise a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3...
August 4, 2018: Clinical and Experimental Immunology
Emma Ahlén Bergman, Ciputra Adijaya Hartana, Markus Johansson, Ludvig B Linton, Sofia Berglund, Martin Hyllienmark, Christian Lundgren, Benny Holmström, Karin Palmqvist, Johan Hansson, Farhood Alamdari, Ylva Huge, Firas Aljabery, Katrine Riklund, Malin E Winerdal, David Krantz, A Ali Zirakzadeh, Per Marits, Louise K Sjöholm, Amir Sherif, Ola Winqvist
BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies...
August 3, 2018: Clinical Epigenetics
Zhiliang Wang, Zheng Wang, Chuanbao Zhang, Xing Liu, Guanzhang Li, Shuai Liu, Lihua Sun, Jingshan Liang, Huimin Hu, Yanwei Liu, Wei Zhang, Tao Jiang
Glioma is the most common malignant tumor that primarily originated from brain tissue. Immune checkpoints have been increasingly emphasized as targets for treating malignant tumors. B7-H3, has been identified as an immune checkpoint which shows potential values for targeting therapies. We set out to characterize the expression pattern and biological function of B7-H3 in brain gliomas via high-throughput data obtained from CGGA and TCGA projects. B7-H3 was upregulated in higher grade gliomas than that in lower grade gliomas in both CGGA and TCGA datasets...
July 20, 2018: Cancer Science
Laura M Beaver, Christiane V Lӧhr, John D Clarke, Sarah T Glasser, Greg W Watson, Carmen P Wong, Zhenzhen Zhang, David E Williams, Roderick H Dashwood, Jackilen Shannon, Philippe Thuillier, Emily Ho
Background: Cruciferous vegetables have been associated with the chemoprevention of cancer. Epigenetic regulators have been identified as important targets for prostate cancer chemoprevention. Treatment of human prostate cancer cells with sulforaphane (SFN), a chemical from broccoli and broccoli sprouts, inhibits epigenetic regulators such as histone deacetylase (HDAC) enzymes, but it is not known whether consumption of a diet high in broccoli sprouts impacts epigenetic mechanisms in an in vivo model of prostate cancer...
March 2018: Current developments in nutrition
Ciputra Adijaya Hartana, Emma Ahlén Bergman, Augusta Broomé, Sofia Berglund, Markus Johansson, Farhood Alamdari, Tomasz Jakubczyk, Ylva Huge, Firas Aljabery, Karin Palmqvist, Benny Holmström, Hans Glise, Katrine Riklund, Amir Sherif, Ola Winqvist
Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but their epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potentials. 53 urothelial urinary bladder cancer (UBC) patients were prospectively recruited. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing...
July 15, 2018: Clinical and Experimental Immunology
Carrie Van Der Weyden, Martine Bagot, Paul Neeson, Phil K Darcy, H Miles Prince
Therapeutic options for mycosis fungoides and Sézary syndrome include a variety of immunomodulatory, epigenetic, and cytotoxic options; however, none has been demonstrated to be efficacious for all patients, or to deliver deep and durable responses to the majority of patients. In this review, we examine the monoclonal antibody, IPH4102, a novel agent for the treatment of cutaneous T-cell lymphoma. Areas covered: In this review, we examine data demonstrating the tissue specificity of KIR3DL2 receptor, which is highly expressed on the malignant cells in cutaneous T-cell lymphoma, including mycosis fungoides and Sézary syndrome...
August 2018: Expert Opinion on Investigational Drugs
Koichi Takahashi, Feng Wang, Kiyomi Morita, Yuanqing Yan, Peter Hu, Pei Zhao, Abdallah Abou Zhar, Chang Jiun Wu, Curtis Gumbs, Latasha Little, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Marisela Mendoza, Erika Thompson, Jianhua Zhang, Courtney D DiNardo, Nitin Jain, Farhad Ravandi, Jorge E Cortes, Guillermo Garcia-Manero, Steven Kornblau, Michael Andreeff, Elias Jabbour, Carlos Bueso-Ramos, Akifumi Takaori-Kondo, Marina Konopleva, Keyur Patel, Hagop Kantarjian, P Andrew Futreal
Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions...
July 10, 2018: Nature Communications
Marike L Broekman, Sybren L N Maas, Erik R Abels, Thorsten R Mempel, Anna M Krichevsky, Xandra O Breakefield
Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth...
August 2018: Nature Reviews. Neurology
R K Foltran, P V G H Amorim, F H Duarte, I P P Grande, A C T B Freire, F P Frassetto, J B Dettoni, V A Alves, I Castro, E B Trarbach, M D Bronstein, R S Jallad
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable...
June 25, 2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
Douae Bensaid, Thibaut Blondy, Sophie Deshayes, Virginie Dehame, Philippe Bertrand, Marc Grégoire, Mohammed Errami, Christophe Blanquart
Background: Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma...
2018: Clinical Epigenetics
Lili Zhang, Bo Pang, Wenbin Zhang, Wei Bai, Weiying Yu, Yuanyuan Li, Wanqing Hua, Wenjun Li, Changgui Kou
BACKGROUND: DNA demethylase is a crucial enzyme in the epigenetic modification and regulation mechanisms of gene transcription. Based on previous assertions that the pathophysiology of schizophrenia is associated with epigenetics, we aimed to explore whether DNA demethylase activity might be related to schizophrenia in northeast China. METHODS: We recruited 25 patients with first-episode schizophrenia and 29 normal controls from a northeast Chinese Han population...
June 1, 2018: Clinical Laboratory
David Cheishvili, Surabhi Parashar, Niaz Mahmood, Ani Arakelian, Richard Kremer, David Goltzman, Moshe Szyf, Shafaat A Rabbani
Osteoporosis is one of the most common age-related progressive bone diseases in elderly people. Approximately one in three women and one in five men are predisposed to developing osteoporosis. In postmenopausal women, a reduction in BMD leads to an increased risk of fractures. In the current study, we delineated the DNA methylation signatures in whole blood samples of postmenopausal osteoporotic women. We obtained whole blood DNA from 22 normal women and 22 postmenopausal osteoporotic women (51 to 89 years old) from the Canadian Multicenter Osteoporosis Study (CaMos) cohort...
June 20, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
A He, Y Ning, Y Wen, Y Cai, K Xu, Y Cai, J Han, L Liu, Y Du, X Liang, P Li, Q Fan, J Hao, X Wang, X Guo, T Ma, F Zhang
Aim: Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage. Patients and Methods: Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California)...
May 2018: Bone & Joint Research
Ghina Chougui, Soundasse Munir-Matloob, Roy Matkovic, Michaël M Martin, Marina Morel, Hichem Lahouassa, Marjorie Leduc, Bertha Cecilia Ramirez, Lucie Etienne, Florence Margottin-Goguet
To evade host immune defences, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) have evolved auxiliary proteins that target cell restriction factors. Viral protein X (Vpx) from the HIV-2/SIVsmm lineage enhances viral infection by antagonizing SAMHD1 (refs 1,2 ), but this antagonism is not sufficient to explain all Vpx phenotypes. Here, through a proteomic screen, we identified another Vpx target-HUSH (TASOR, MPP8 and periphilin)-a complex involved in position-effect variegation 3 . HUSH downregulation by Vpx is observed in primary cells and HIV-2-infected cells...
June 11, 2018: Nature Microbiology
Hanna Leins, Medhanie Mulaw, Karina Eiwen, Vadim Sakk, Ying Liang, Michael Denkinger, Hartmut Geiger, Reinhold Schirmbeck
Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN...
June 11, 2018: Blood
Magdalena Dryglewska, Bogdan Kolarz, Maria Majdan
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that results in uncontrolled immune system activation and overproduction of autoantibodies. The pathogenesis of the disease is complex and not fully understood, nevertheless, genetic and environmental factors play an important role. So far, about 30 genes have been identified to be involved in the SLE pathomechanism. However, not all genetically predisposed individuals develop the disease. This phenomenon can be associated with epigenetic changes that occur under the influence of environmental factors...
2018: Wiadomości Lekarskie: Organ Polskiego Towarzystwa Lekarskiego
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