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Iannis Aifantis

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https://www.readbyqxmd.com/read/28518167/rna-binding-proteins-the-guardians-of-the-marginal-zone
#1
Palaniraja Thandapani, Beatriz Aranda-Orgilles, Iannis Aifantis
No abstract text is available yet for this article.
May 18, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28440315/tet2-loss-leads-to-hypermutagenicity-in-haematopoietic-stem-progenitor-cells
#2
Feng Pan, Thomas S Wingo, Zhigang Zhao, Rui Gao, Hideki Makishima, Guangbo Qu, Li Lin, Miao Yu, Janice R Ortega, Jiapeng Wang, Aziz Nazha, Li Chen, Bing Yao, Can Liu, Shi Chen, Ophelia Weeks, Hongyu Ni, Brittany Lynn Phillips, Suming Huang, Jianlong Wang, Chuan He, Guo-Min Li, Tomas Radivoyevitch, Iannis Aifantis, Jaroslaw P Maciejewski, Feng-Chun Yang, Peng Jin, Mingjiang Xu
TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2(-/-) mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2(-/-) tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies...
April 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28272987/opposing-functions-of-h2bk120-ubiquitylation-and-h3k79-methylation-in-the-regulation-of-pluripotency-by-the-paf1-complex
#3
Alexandros Strikoudis, Charalampos Lazaris, Panagiotis Ntziachristos, Aristotelis Tsirigos, Iannis Aifantis
Maintenance of stem cell plasticity is determined by the ability to balance opposing forces that control gene expression. Regulation of transcriptional networks, signaling cues and chromatin-modifying mechanisms constitute crucial determinants of tissue equilibrium. Histone modifications can affect chromatin compaction, therefore co-transcriptional events that influence their deposition determine the propensities towards quiescence, self-renewal, or cell specification. The Paf1 complex (Paf1C) is a critical regulator of RNA PolII elongation that controls gene expression and deposition of histone modifications, however few studies have focused on its role affecting stem cell fate decisions...
March 8, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28056762/hic-bench-comprehensive-and-reproducible-hi-c-data-analysis-designed-for-parameter-exploration-and-benchmarking
#4
Charalampos Lazaris, Stephen Kelly, Panagiotis Ntziachristos, Iannis Aifantis, Aristotelis Tsirigos
BACKGROUND: Chromatin conformation capture techniques have evolved rapidly over the last few years and have provided new insights into genome organization at an unprecedented resolution. Analysis of Hi-C data is complex and computationally intensive involving multiple tasks and requiring robust quality assessment. This has led to the development of several tools and methods for processing Hi-C data. However, most of the existing tools do not cover all aspects of the analysis and only offer few quality assessment options...
January 5, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28007775/beating-the-clock-in-t-cell-acute-lymphoblastic-leukemia
#5
William L Carroll, Iannis Aifantis, Elizabeth Raetz
CDK4/6 inhibition was synergistic with dexamethasone and everolimus but antagonistic with conventional chemotherapy in T-cell acute lymphoblastic leukemia (T-ALL) preclinical models. Cyclin-dependent kinase inhibition in combination with glucocorticoids and mTOR inhibition offers a unique therapeutic opportunity in T-ALL. Clin Cancer Res; 23(4); 873-5. ©2016 AACRSee related article by Pikman et al., p. 1012.
February 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27939598/alternative-roles-for-oxidized-mcs-and-tets
#6
REVIEW
Luisa Cimmino, Iannis Aifantis
Ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine (5mC) to form stable or transient modifications (oxi-mCs) in the mammalian genome. Genome-wide mapping and protein interaction studies have shown that 5mC and oxi-mCs have unique distribution patterns and alternative roles in gene expression. In addition, oxi-mCs may interact with specific chromatin regulators, transcription factors and DNA repair proteins to maintain genomic integrity or alter DNA replication and transcriptional elongation rates...
December 7, 2016: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/27776115/deregulation-of-dux4-and-erg-in-acute-lymphoblastic-leukemia
#7
Jinghui Zhang, Kelly McCastlain, Hiroki Yoshihara, Beisi Xu, Yunchao Chang, Michelle L Churchman, Gang Wu, Yongjin Li, Lei Wei, Ilaria Iacobucci, Yu Liu, Chunxu Qu, Ji Wen, Michael Edmonson, Debbie Payne-Turner, Kerstin B Kaufmann, Shin-Ichiro Takayanagi, Erno Wienholds, Esmé Waanders, Panagiotis Ntziachristos, Sofia Bakogianni, Jingjing Wang, Iannis Aifantis, Kathryn G Roberts, Jing Ma, Guangchun Song, John Easton, Heather L Mulder, Xiang Chen, Scott Newman, Xiaotu Ma, Michael Rusch, Pankaj Gupta, Kristy Boggs, Bhavin Vadodaria, James Dalton, Yanling Liu, Marcus L Valentine, Li Ding, Charles Lu, Robert S Fulton, Lucinda Fulton, Yashodhan Tabib, Kerri Ochoa, Meenakshi Devidas, Deqing Pei, Cheng Cheng, Jun Yang, William E Evans, Mary V Relling, Ching-Hon Pui, Sima Jeha, Richard C Harvey, I-Ming L Chen, Cheryl L Willman, Guido Marcucci, Clara D Bloomfield, Jessica Kohlschmidt, Krzysztof Mrózek, Elisabeth Paietta, Martin S Tallman, Wendy Stock, Matthew C Foster, Janis Racevskis, Jacob M Rowe, Selina Luger, Steven M Kornblau, Sheila A Shurtleff, Susana C Raimondi, Elaine R Mardis, Richard K Wilson, John E Dick, Stephen P Hunger, Mignon L Loh, James R Downing, Charles G Mullighan
Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion...
December 2016: Nature Genetics
https://www.readbyqxmd.com/read/27749823/regulation-of-transcriptional-elongation-in-pluripotency-and-cell-differentiation-by-the-phd-finger-protein-phf5a
#8
Alexandros Strikoudis, Charalampos Lazaris, Thomas Trimarchi, Antonio L Galvao Neto, Yan Yang, Panagiotis Ntziachristos, Scott Rothbart, Shannon Buckley, Igor Dolgalev, Matthias Stadtfeld, Brian D Strahl, Brian D Dynlacht, Aristotelis Tsirigos, Iannis Aifantis
Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci...
November 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27668798/the-ubiquitin-ligase-huwe1-regulates-the-maintenance-and-lymphoid-commitment-of-hematopoietic-stem-cells
#9
Bryan King, Francesco Boccalatte, Kelly Moran-Crusio, Elmar Wolf, Jingjing Wang, Clarisse Kayembe, Charalampos Lazaris, Xiaofeng Yu, Beatriz Aranda-Orgilles, Anna Lasorella, Iannis Aifantis
Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (Mycn(M)), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations...
November 2016: Nature Immunology
https://www.readbyqxmd.com/read/27570068/med12-regulates-hsc-specific-enhancers-independently-of-mediator-kinase-activity-to-control-hematopoiesis
#10
Beatriz Aranda-Orgilles, Ricardo Saldaña-Meyer, Eric Wang, Eirini Trompouki, Anne Fassl, Stephanie Lau, Jasper Mullenders, Pedro P Rocha, Ramya Raviram, María Guillamot, María Sánchez-Díaz, Kun Wang, Clarisse Kayembe, Nan Zhang, Leonela Amoasii, Avik Choudhuri, Jane A Skok, Markus Schober, Danny Reinberg, Piotr Sicinski, Heinrich Schrewe, Aristotelis Tsirigos, Leonard I Zon, Iannis Aifantis
Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality...
December 1, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27478938/emerging-concepts-of-epigenetic-dysregulation-in-hematological-malignancies
#11
REVIEW
Panagiotis Ntziachristos, Omar Abdel-Wahab, Iannis Aifantis
The past decade brought a revolution in understanding of the structure, topology and disease-inducing lesions of RNA and DNA, fueled by unprecedented progress in next-generation sequencing. This technological revolution has also affected understanding of the epigenome and has provided unique opportunities for the analysis of DNA and histone modifications, as well as the first map of the non-protein-coding genome and three-dimensional (3D) chromosomal interactions. Overall, these advances have facilitated studies that combine genetic, transcriptomics and epigenomics data to address a wide range of issues ranging from understanding the role of the epigenome in development to targeting the transcription of noncoding genes in human cancer...
September 2016: Nature Immunology
https://www.readbyqxmd.com/read/27424808/mutant-idh1-downregulates-atm-and-alters-dna-repair-and-sensitivity-to-dna-damage-independent-of-tet2
#12
Satoshi Inoue, Wanda Y Li, Alan Tseng, Isabel Beerman, Andrew J Elia, Sean C Bendall, François Lemonnier, Ken J Kron, David W Cescon, Zhenyue Hao, Evan F Lind, Naoya Takayama, Aline C Planello, Shu Yi Shen, Alan H Shih, Dana M Larsen, Qinxi Li, Bryan E Snow, Andrew Wakeham, Jillian Haight, Chiara Gorrini, Christian Bassi, Kelsie L Thu, Kiichi Murakami, Alisha R Elford, Takeshi Ueda, Kimberly Straley, Katharine E Yen, Gerry Melino, Luisa Cimmino, Iannis Aifantis, Ross L Levine, Daniel D De Carvalho, Mathieu Lupien, Derrick J Rossi, Garry P Nolan, Rob A Cairns, Tak W Mak
Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2...
August 8, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27239026/active-and-inactive-enhancers-cooperate-to-exert-localized-and-long-range-control-of-gene-regulation
#13
Charlotte Proudhon, Valentina Snetkova, Ramya Raviram, Camille Lobry, Sana Badri, Tingting Jiang, Bingtao Hao, Thomas Trimarchi, Yuval Kluger, Iannis Aifantis, Richard Bonneau, Jane A Skok
V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component...
June 7, 2016: Cell Reports
https://www.readbyqxmd.com/read/27019871/the-impact-of-dna-methylation-in-hematopoietic-malignancies
#14
Maria Guillamot, Luisa Cimmino, Iannis Aifantis
Aberrant DNA methylation is a characteristic feature of cancer including blood malignancies. Mutations in the DNA methylation regulators DNMT3A, TET1/2 and IDH1/2 are recurrent in leukemia and lymphoma. Specific and distinct DNA methylation patterns characterize subtypes of AML and lymphoma. Regulatory regions such as promoter CpG islands, CpG shores and enhancers show changes in methylation during transformation. However, the reported poor correlation between changes in methylation and gene expression in many mouse models and human studies reflects the complexity in the precise molecular mechanism for why aberrant DNA methylation promotes malignancies...
February 1, 2016: Trends in Cancer
https://www.readbyqxmd.com/read/26950094/genomic-analysis-identifies-new-drivers-and-progression-pathways-in-skin-basal-cell-carcinoma
#15
Ximena Bonilla, Laurent Parmentier, Bryan King, Fedor Bezrukov, Gürkan Kaya, Vincent Zoete, Vladimir B Seplyarskiy, Hayley J Sharpe, Thomas McKee, Audrey Letourneau, Pascale G Ribaux, Konstantin Popadin, Nicole Basset-Seguin, Rouaa Ben Chaabene, Federico A Santoni, Maria A Andrianova, Michel Guipponi, Marco Garieri, Carole Verdan, Kerstin Grosdemange, Olga Sumara, Martin Eilers, Iannis Aifantis, Olivier Michielin, Frederic J de Sauvage, Stylianos E Antonarakis, Sergey I Nikolaev
Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes...
April 2016: Nature Genetics
https://www.readbyqxmd.com/read/26613412/the-cul4-ddb1-ubiquitin-ligase-complex-controls-adult-and-embryonic-stem-cell-differentiation-and-homeostasis
#16
Jie Gao, Shannon M Buckley, Luisa Cimmino, Maria Guillamot, Alexandros Strikoudis, Yong Cang, Stephen P Goff, Iannis Aifantis
Little is known on post-transcriptional regulation of adult and embryonic stem cell maintenance and differentiation. Here we characterize the role of Ddb1, a component of the CUL4-DDB1 ubiquitin ligase complex. Ddb1 is highly expressed in multipotent hematopoietic progenitors and its deletion leads to abrogation of both adult and fetal hematopoiesis, targeting specifically transiently amplifying progenitor subsets. However, Ddb1 deletion in non-dividing lymphocytes has no discernible phenotypes. Ddb1 silencing activates Trp53 pathway and leads to significant effects on cell cycle progression and rapid apoptosis...
November 27, 2015: ELife
https://www.readbyqxmd.com/read/26574507/cardiac-myocyte-klf5-regulates-ppara-expression-and-cardiac-function
#17
Konstantinos Drosatos, Nina M Pollak, Christine J Pol, Panagiotis Ntziachristos, Florian Willecke, Mesele-Christina Valenti, Chad M Trent, Yunying Hu, Shaodong Guo, Iannis Aifantis, Ira J Goldberg
RATIONALE: Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown. OBJECTIVE: To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara...
January 22, 2016: Circulation Research
https://www.readbyqxmd.com/read/26438359/cohesin-loss-alters-adult-hematopoietic-stem-cell-homeostasis-leading-to-myeloproliferative-neoplasms
#18
Jasper Mullenders, Beatriz Aranda-Orgilles, Priscillia Lhoumaud, Matthew Keller, Juhee Pae, Kun Wang, Clarisse Kayembe, Pedro P Rocha, Ramya Raviram, Yixiao Gong, Prem K Premsrirut, Aristotelis Tsirigos, Richard Bonneau, Jane A Skok, Luisa Cimmino, Daniela Hoehn, Iannis Aifantis
The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability...
October 19, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26426760/emerging-roles-for-the-fbxw7-ubiquitin-ligase-in-leukemia-and-beyond
#19
REVIEW
Nikos Kourtis, Alexandros Strikoudis, Iannis Aifantis
Protein degradation plays key roles in diverse pathways in cell division, growth and differentiation. Aberrant stabilization of crucial proteins participating in oncogenic pathways is often observed in cancer. The importance of proper protein turnover is exemplified by the SCF(Fbxw7) ubiquitin ligase, which is frequently mutated in human cancer, including T cell acute lymphoblastic leukemia. Recent studies have revealed novel substrates of Fbxw7 and shed light on its role on differentiation of stem cells and expansion of stem-cell-like cells driving tumorigenesis...
December 2015: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/26194287/erratum-tet1-is-a-tumor-suppressor-of-hematopoietic-malignancy
#20
Luisa Cimmino, Meelad M Dawlaty, Delphine Ndiaye-Lobry, Yoon Sing Yap, Sofia Bakogianni, Yiting Yu, Sanchari Bhattacharyya, Rita Shaknovich, Huimin Geng, Camille Lobry, Jasper Mullenders, Bryan King, Thomas Trimarchi, Beatriz Aranda-Orgilles, Cynthia Liu, Steven Shen, Amit K Verma, Rudolf Jaenisch, Iannis Aifantis
No abstract text is available yet for this article.
August 2015: Nature Immunology
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