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https://www.readbyqxmd.com/read/28930682/chemically-induced-degradation-of-the-oncogenic-transcription-factor-bcl6
#1
Nina Kerres, Steffen Steurer, Stefanie Schlager, Gerd Bader, Helmut Berger, Maureen Caligiuri, Christian Dank, John R Engen, Peter Ettmayer, Bernhard Fischerauer, Gerlinde Flotzinger, Daniel Gerlach, Thomas Gerstberger, Teresa Gmaschitz, Peter Greb, Bingsong Han, Elizabeth Heyes, Roxana E Iacob, Dirk Kessler, Heike Kölle, Lyne Lamarre, David R Lancia, Simon Lucas, Moriz Mayer, Katharina Mayr, Nikolai Mischerikow, Katja Mück, Christoph Peinsipp, Oliver Petermann, Ulrich Reiser, Dorothea Rudolph, Klaus Rumpel, Carina Salomon, Dirk Scharn, Renate Schnitzer, Andreas Schrenk, Norbert Schweifer, Diane Thompson, Elisabeth Traxler, Roland Varecka, Tilman Voss, Alexander Weiss-Puxbaum, Sandra Winkler, Xiaozhang Zheng, Andreas Zoephel, Norbert Kraut, Darryl McConnell, Mark Pearson, Manfred Koegl
The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930662/the-kinase-mtorc1-promotes-the-generation-and-suppressive-function-of-follicular-regulatory-t-cells
#2
Lifan Xu, Qizhao Huang, Haoqiang Wang, Yaxing Hao, Qiang Bai, Jianjun Hu, Yiding Li, Pengcheng Wang, Xiangyu Chen, Ran He, Bingshou Li, Xia Yang, Tingting Zhao, Yanyan Zhang, Yifei Wang, Juanjuan Ou, Houjie Liang, Yuzhang Wu, Xinyuan Zhou, Lilin Ye
Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28930660/the-irf4-gene-regulatory-module-functions-as-a-read-write-integrator-to-dynamically-coordinate-t%C3%A2-helper-cell-fate
#3
Veena Krishnamoorthy, Sunil Kannanganat, Mark Maienschein-Cline, Sarah L Cook, Jianjun Chen, Neil Bahroos, Evelyn Sievert, Emily Corse, Anita Chong, Roger Sciammas
Transcriptional regulation during CD4(+) T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28929458/backbone-resonance-assignment-of-the-bcl6-btb-poz-domain
#4
Li-Ying Lin, S E Evans, L Fairall, John W R Schwabe, Simon D Wagner, Frederick W Muskett
BCL6 is a transcriptional repressor. Two domains of the protein, the N-terminal BTB-POZ domain and the RD2 domain are responsible for recruitment of co-repressor molecules and histone deacetylases. The BTB-POZ domain is found in a large and diverse range of proteins that play important roles in development, homeostasis and neoplasia. Crystal structures of several BTB-POZ domains, including BCL6 have been determined. The BTB-POZ domain of BCL6 not only mediates dimerisation but is also responsible for recruitment of co-repressors such as SMRT, NCOR and BCOR...
September 19, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28928451/corrigendum-bcl6-sets-a-threshold-for-antiviral-signaling-by-restraining-irf7-transcriptional-program
#5
Feng Xu, Yanhua Kang, Ningtong Zhuang, Zhe Lu, Hang Zhang, Dakang Xu, Yina Ding, Hongping Yin, Liyun Shi
This corrects the article DOI: 10.1038/srep18778.
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28926365/primary-cutaneous-diffuse-large-b-cell-lymphoma-leg-type-with-spontaneous-regression-after-biopsy
#6
Gabriel Marrero-Alemán, Társila Montenegro-Dámaso, Yeray Peñate
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) represents approximately 20% of cutaneous B lymphomas with an intermediate prognosis. Spontaneous regression is uncommon; there are only 2 published cases. An 83-year-old woman presented 2 orange erythematous nodules on the back of her right leg with an elastic consistency, infiltrated, painful to the touch, and of an 8-month evolution. A histological examination revealed a dense cellular dermo-hypodermic infiltrate sparing the papillary dermis, composed of large cells with immunoblast and centroblast morphology and frequent mitosis...
October 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28922406/loss-of-liver-specific-and-sexually-dimorphic-gene-expression-by-aryl-hydrocarbon-receptor-activation-in-c57bl-6-mice
#7
Rance Nault, Kelly A Fader, Jack R Harkema, Tim Zacharewski
The aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that mediates a broad spectrum of species-, strain-, sex-, age-, tissue-, and cell-specific responses elicited by structurally diverse ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dose-dependent effects on liver-specific and sexually dimorphic gene expression were examined in male and female mice gavaged with TCDD every 4 days for 28 or 92 days. RNA-seq data revealed the coordinated repression of 181 genes predominately expressed in the liver including albumin (3...
2017: PloS One
https://www.readbyqxmd.com/read/28888925/follicular-helper-t-cells-are-essential-for-the-elimination-of-plasmodium-infection
#8
Damián Pérez-Mazliah, Minh Phuong Nguyen, Caroline Hosking, Sarah McLaughlin, Matthew D Lewis, Irene Tumwine, Prisca Levy, Jean Langhorne
CD4(+) follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P...
September 4, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28887367/tfr-cells-lack-il-2r%C3%AE-but-express-decoy-il-1r2-and-il-1ra-and-suppress-the-il-1-dependent-activation-of-tfh-cells
#9
Paul-Gydeon G Ritvo, Guillame Churlaud, Valentin Quiniou, Laura Florez, Faustine Brimaud, Gwladys Fourcade, Encarnita Mariotti-Ferrandiz, David Klatzmann
Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25(+) cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25(-), in mice and humans...
September 8, 2017: Science Immunology
https://www.readbyqxmd.com/read/28875978/il4-and-il21-cooperate-to-induce-the-high-bcl6-protein-level-required-for-germinal-center-formation
#10
Stéphane Chevrier, Tobias Kratina, Dianne Emslie, David M Tarlinton, Lynn M Corcoran
Bcl6 is a transcriptional repressor and critical mediator of the germinal center reaction during a T cell dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B cell receptor causes rapid proteasomal degradation of Bcl6...
September 6, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28868942/myc-immunohistochemical-and-cytogenetic-analysis-are-required-for-identification-of-clinically-relevant-aggressive-b-cell-lymphoma-subtypes
#11
Philipp W Raess, Stephen R Moore, Michael J Cascio, Jennifer Dunlap, Guang Fan, Ken Gatter, Susan B Olson, Rita M Braziel
Accurate subclassification of aggressive B cell lymphomas (ABCLs) requires integration of morphologic, immunohistochemical (IHC), and cytogenetic information. Optimal strategies have not been well defined for diagnosis of high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBLwR) and double expressor lymphomas with MYC and BCL2 protein overexpression. One hundred and eighty seven ABCLs were investigated with complete IHC and FISH analysis. Morphologic and IHC analysis was insufficient to identify clinically relevant HGBLwR...
September 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28844114/the-clinicopathologic-spectrum-of-mature-aggressive-b-cell-lymphomas
#12
REVIEW
Lisa Rimsza, Stefania Pittaluga, Stephan Dirnhofer, Christiane Copie-Bergman, Laurence de Leval, Fabio Facchetti, Stefano Pileri, Andreas Rosenwald, Andrew Wotherspoon, Falko Fend
Our understanding of mature aggressive B cell lymphomas has evolved significantly in the last years as reflected in the 2016 update of the WHO lymphoma classification. A main topic of the 2016 European Association for Haematopathology/Society of Hematopathology lymphoma workshop in Basel therefore was the clinicopathological spectrum of mature aggressive B cell lymphomas with the exception of conventional diffuse large B cell lymphoma. In this review, we summarize two sessions dedicated to "high-grade B cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (so-called double/triple-hit lymphomas)" and "high-grade B cell lymphomas, NOS" as defined in the 2016 update of the WHO lymphoma classification, Burkitt lymphoma and related neoplasms, and terminally differentiated aggressive B cell lymphomas...
August 26, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28838616/molecular-analysis-of-immunoglobulin-variable-genes-supports-a-germinal-center-experienced-normal-counterpart-in-primary-cutaneous-diffuse-large-b-cell-lymphoma-leg-type
#13
Anne Pham-Ledard, Martina Prochazkova-Carlotti, Mélanie Deveza, Marie-Pierre Laforet, Marie Beylot-Barry, Béatrice Vergier, Marie Parrens, Jean Feuillard, Jean-Philippe Merlio, Nathalie Gachard
BACKGROUND: Immunophenotype of primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL-LT) suggests a germinal center-experienced B lymphocyte (BCL2+ MUM1+ BCL6+/-). OBJECTIVES: As maturation history of B-cell is "imprinted" during B-cell development on the immunoglobulin gene sequence, we studied the structure and sequence of the variable part of the genes (IGHV, IGLV, IGKV), immunoglobulin surface expression and features of class switching in order to determine the PCLBCL-LT cell of origin...
July 26, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28827447/internal-deletion-of-bcor-reveals-a-tumor-suppressor-function-for-bcor-in-t-lymphocyte-malignancies
#14
Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama
Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (Bcor(ΔE4/y) ) compromised the repopulating capacity of hematopoietic stem cells, Bcor(ΔE4/y) thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner...
August 21, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28811467/the-mtorc1-4e-bp-eif4e-axis-controls-de-novo-bcl6-protein-synthesis-in-t-cells-and-systemic-autoimmunity
#15
Woelsung Yi, Sanjay Gupta, Edd Ricker, Michela Manni, Rolf Jessberger, Yurii Chinenov, Henrik Molina, Alessandra B Pernis
Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute to the expression of T helper (TH) lineage-defining factors is unknown. Tight regulation of Bcl6 expression, an essential transcription factor for T follicular helper (TFH) cells, is critical as aberrant TFH cell expansion is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we show that lack of the SLE risk variant Def6 results in deregulation of Bcl6 protein synthesis in T cells as a result of enhanced activation of the mTORC1-4E-BP-eIF4E axis, secondary to aberrant assembly of a raptor-p62-TRAF6 complex...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28776574/increased-myc-copy-number-is-an-independent-prognostic-factor-in-patients-with-diffuse-large-b-cell-lymphoma
#16
Andrés E Quesada, L Jeffrey Medeiros, Parth A Desai, Pei Lin, Jason R Westin, Huda M Hawsawi, Peng Wei, Guilin Tang, Adam C Seegmiller, Nishitha M Reddy, C Cameron Yin, Wei Wang, Jie Xu, Roberto N Miranda, Zhuang Zuo, Shaoying Li
Patients with double-hit or triple-hit lymphoma have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma without MYC rearrangement. However, the prognostic importance of extra copies of MYC, BCL2, or BCL6 has not been fully explored. We studied 663 patients with de novo diffuse large B-cell lymphoma in whom the status of MYC/8q24, BCL2/18q21, and BCL6/3q27 were assessed by fluorescence in situ hybridization. Cases of double or triple extra copy lymphoma were defined by the presence of increased MYC copies and increased BCL2 and/or BCL6 copies or rearrangement...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28766546/-diffuse-large-b-cell-lymphoma-with-concomitant-c-myc-and-bcl6-gene-rearrangements-with-primary-skin-involvement-a-case-report-and-a-review-of-literature
#17
N G Gabeeva, D A Koroleva, A V Belyaeva, N G Chernova, L A Kuzmina, A B Sudarikov, T N Obukhova, A M Kovrigina, E E Zvonkov, V G Savchenko
Double-hit lymphoma (DHL) is a rare aggressive B-cell lymphoma with concomitant c-MYC, BCL2 or BCL6 gene rearrangements, which is characterized by the high frequency of extranodal lesions and by resistance to chemotherapy. The median survival does not exceed 18 months in patients with this disease. The majority of DHL is represented by с-MYC/BCL2 cases. The combination of c-MYC/BCL6 occurs rarely (5-8%). The paper describes a case of DHL with concomitant c-MYC and BCL6 gene rearrangements, which mimics diffuse large B-cell lymphoma, leg-type...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28765546/integrative-whole-genome-sequence-analysis-reveals-roles-of-regulatory-mutations-in-bcl6-and-bcl2-in-follicular-lymphoma
#18
Kirill Batmanov, Wei Wang, Magnar Bjørås, Jan Delabie, Junbai Wang
The contribution of mutations in regulatory regions to tumorigenesis has been the subject of many recent studies. We propose a new framework for integrative analysis of genome-wide sequencing data by considering diverse genetic information. This approach is applied to study follicular lymphoma (FL), a disease for which little is known about the contribution of regulatory gene mutations. Results from a test FL cohort revealed three novel highly recurrent regulatory mutation blocks near important genes implicated in FL, BCL6 and BCL2...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28760529/discovery-of-a-novel-b-cell-lymphoma-6-bcl6-corepressor-interaction-inhibitor-by-utilizing-structure-based-drug-design
#19
Takeshi Yasui, Takeshi Yamamoto, Nozomu Sakai, Kouhei Asano, Takafumi Takai, Yayoi Yoshitomi, Melinda Davis, Terufumi Takagi, Kotaro Sakamoto, Satoshi Sogabe, Yusuke Kamada, Weston Lane, Gyorgy Snell, Masashi Iwata, Masayuki Goto, Hiroshi Inooka, Jun-Ichi Sakamoto, Yoshihisa Nakada, Yasuhiro Imaeda
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0...
September 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28754906/kras-activation-and-over-expression-of-sirt1-bcl6-contributes-to-the-pathogenesis-of-endometriosis-and-progesterone-resistance
#20
Jung-Yoon Yoo, Tae Hoon Kim, Asgerally T Fazleabas, Wilder A Palomino, Soo Hyun Ahn, Chandrakant Tayade, David P Schammel, Steven L Young, Jae-Wook Jeong, Bruce A Lessey
Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to over-expression of the oncogene BCL6 and stabilization of hypoxia-induced factor 1 alpha (HIF-1α). Here we report coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, in the eutopic endometrium from women with endometriosis throughout the menstrual cycle...
July 28, 2017: Scientific Reports
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