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Iannis Aifantis

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https://www.readbyqxmd.com/read/27776115/deregulation-of-dux4-and-erg-in-acute-lymphoblastic-leukemia
#1
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...
October 24, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27749823/regulation-of-transcriptional-elongation-in-pluripotency-and-cell-differentiation-by-the-phd-finger-protein-phf5a
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/26058075/cxcl12-producing-vascular-endothelial-niches-control-acute-t-cell-leukemia-maintenance
#15
Lauren A Pitt, Anastasia N Tikhonova, Hai Hu, Thomas Trimarchi, Bryan King, Yixiao Gong, Marta Sanchez-Martin, Aris Tsirigos, Dan R Littman, Adolfo A Ferrando, Sean J Morrison, David R Fooksman, Iannis Aifantis, Susan R Schwab
The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts...
June 8, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25965569/srsf2-mutations-contribute-to-myelodysplasia-by-mutant-specific-effects-on-exon-recognition
#16
Eunhee Kim, Janine O Ilagan, Yang Liang, Gerrit M Daubner, Stanley C-W Lee, Aravind Ramakrishnan, Yue Li, Young Rock Chung, Jean-Baptiste Micol, Michele E Murphy, Hana Cho, Min-Kyung Kim, Ahmad S Zebari, Shlomzion Aumann, Christopher Y Park, Silvia Buonamici, Peter G Smith, H Joachim Deeg, Camille Lobry, Iannis Aifantis, Yorgo Modis, Frederic H-T Allain, Stephanie Halene, Robert K Bradley, Omar Abdel-Wahab
Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators...
May 11, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25873173/mutational-cooperativity-linked-to-combinatorial-epigenetic-gain-of-function-in-acute-myeloid-leukemia
#17
Alan H Shih, Yanwen Jiang, Cem Meydan, Kaitlyn Shank, Suveg Pandey, Laura Barreyro, Ileana Antony-Debre, Agnes Viale, Nicholas Socci, Yongming Sun, Alexander Robertson, Magali Cavatore, Elisa de Stanchina, Todd Hricik, Franck Rapaport, Brittany Woods, Chen Wei, Megan Hatlen, Muhamed Baljevic, Stephen D Nimer, Martin Tallman, Elisabeth Paietta, Luisa Cimmino, Iannis Aifantis, Ulrich Steidl, Chris Mason, Ari Melnick, Ross L Levine
Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus...
April 13, 2015: Cancer Cell
https://www.readbyqxmd.com/read/25867473/tet1-is-a-tumor-suppressor-of-hematopoietic-malignancy
#18
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
The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair...
June 2015: Nature Immunology
https://www.readbyqxmd.com/read/25862091/the-methylcytosine-dioxygenase-tet2-promotes-dna-demethylation-and-activation-of-cytokine-gene-expression-in-t-cells
#19
Kenji Ichiyama, Tingting Chen, Xiaohu Wang, Xiaowei Yan, Byung-Seok Kim, Shinya Tanaka, Delphine Ndiaye-Lobry, Yuhua Deng, Yanli Zou, Pan Zheng, Qiang Tian, Iannis Aifantis, Lai Wei, Chen Dong
Epigenetic regulation of lineage-specific genes is important for the differentiation and function of T cells. Ten-eleven translocation (Tet) proteins catalyze 5-methylcytosine (5 mC) conversion to 5-hydroxymethylcytosine (5 hmC) to mediate DNA demethylation. However, the roles of Tet proteins in the immune response are unknown. Here, we characterized the genome-wide distribution of 5 hmC in CD4(+) T cells and found that 5 hmC marks putative regulatory elements in signature genes associated with effector cell differentiation...
April 21, 2015: Immunity
https://www.readbyqxmd.com/read/25759017/the-pre-bcr-to-the-rescue-therapeutic-targeting-of-pre-b-cell-all
#20
COMMENT
Thomas Trimarchi, Iannis Aifantis
Pre B-ALL is an aggressive cancer of the blood for which treatment of patients with relapsed and refractory disease remains a challenge. In this issue of Cancer Cell, Geng and colleagues surveyed the activation status of the pre-B cell receptor and comprehensively investigated downstream signaling mechanisms currently targetable with small molecule inhibitors.
March 9, 2015: Cancer Cell
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