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Yaoyao Shi, Yue Kuai, Lizhen Lei, Yuanyuan Weng, Friederike Berberich- Siebelt, Xinxia Zhang, Jinjie Wang, Yuan Zhou, Xin Jiang, Guoping Ren, Hongyang Pan, Zhengrong Mao, Ren Zhou
Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6...
October 15, 2016: Oncotarget
Zijun Y Xu-Monette, Ling Li, John C Byrd, Kausar J Jabbar, Ganiraju C Manyam, Charlotte Maria de Winde, Michiel van den Brand, Alexandar Tzankov, Carlo Visco, Jing Wang, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L Richards, Eric D Hsi, William W L Choi, Jooryung Huh, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Ben M Parsons, Jane N Winter, Michael Wang, Fredrick B Hagemeister, Miguel A Piris, J Han van Krieken, L Jeffrey Medeiros, Yong Li, Annemiek B van Spriel, Ken H Young
CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B-cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. In this study, we assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab-CHOP and 231 patients treated with CHOP chemotherapy. We found CD37 loss (CD37(-)) in ~60% of DLBCL predicted significantly decreased survival rates in R-CHOP-treated patients, independent of the International Prognostic Index (IPI), germinal-center-B-cell-like (GCB)/activated-B-cell-like (ABC) cell-of-origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37(-), including TP53 mutation, NF-κB(high), Myc(high), p-STAT3(high), survivin(high), p63(-), and BCL6 translocation...
October 19, 2016: Blood
Rohit Mathur, Lalit Sehgal, Ondrej Havranek, Stefan Köhrer, Tamer Khashab, Neeraj Jain, Jan A Burger, Sattva S Neelapu, R Eric Davis, Felipe Samaniego
Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in-vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients treated with R-CHOP...
October 14, 2016: Haematologica
Satoru Yamasaki, Kanako Shimizu, Kohei Kometani, Maki Sakurai, Masami Kawamura, Shin-Ichiro Fujii
An induction of long-term cellular and humoral immunity is for the goal of vaccines, but the combination of antigens and adjuvant remain unclear. Here, we show, using a cellular vaccine carrying foreign protein antigen plus iNKT cell glycolipid antigen, designated as artificial adjuvant vector cells (aAVCs), that mature XCR1(-) DCs in situ elicit not only ordinal antigen-specific CD4(+)T cells, but also CD4(+) Tfh and germinal center, resulted in inducing long-term antibody production. As a mechanism for leading the long-term antibody production by aAVC, memory CD4(+) Tfh cells but not iNKTfh cells played an important role in a Bcl6 dependent manner...
October 14, 2016: Scientific Reports
Young Uk Kim, Byung-Seok Kim, Hoyong Lim, Rick A Wetsel, Yeonseok Chung
CXCR5⁺ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of Foxp3⁺ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in Foxp3⁺ Treg cells induced a stable expression of functional CXCR5 on their surface...
October 17, 2016: Biomolecules & Therapeutics
Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia-Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S Doane, Xabier Agirre Ena, Matt Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W Scott, Kristy R Stengel, Janice E Kranz, Edward Holson, Sneh Sharma, James W Young, Chi-Shuen Chu, Robert G Roeder, Rita Shaknovich, Scott W Hiebert, Randy D Gascoyne, Wayne Tam, Olivier Elemento, Hans-Guido Wendel, Ari M Melnick
Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates development of germinal center derived lymphomas in mice. In both human and murine lymphomas CREBBP loss of function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses including class II MHC. Mechanistically, CREBBP regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we find bind extensively to MHC class II loci...
October 12, 2016: Cancer Discovery
Mayu Morita, Shigeyuki Yoshida, Ryotaro Iwasaki, Tetsuro Yasui, Yuiko Sato, Tami Kobayashi, Ryuichi Watanabe, Takatsugu Oike, Kana Miyamoto, Masamichi Takami, Keiko Ozato, Chu-Xia Deng, Hiroyuki Aburatani, Sakae Tanaka, Akihiko Yoshimura, Yoshiaki Toyama, Morio Matsumoto, Masaya Nakamura, Hiromasa Kawana, Taneaki Nakagawa, Takeshi Miyamoto
Bone homeostasis is maintained as a delicate balance between bone-resorption and bone-formation, which are coupled to maintain appropriate bone mass. A critical question is how bone-resorption is terminated to allow bone-formation to occur. Here, we show that TGFβs inhibit osteoclastogenesis and maintain bone-mass through Smad4 activity in osteoclasts. We found that latent-TGFβ1 was activated by osteoclasts to inhibit osteoclastogenesis. Osteoclast-specific Smad4 conditional knockout mice (Smad4-cKO) exhibited significantly reduced bone-mass and elevated osteoclast formation relative to controls...
October 12, 2016: Scientific Reports
Allison Rosenthal, Anas Younes
Diffuse large B-cell lymphomas with aberrations in MYC, BCL2 and/or BCL6 by genetic alterations or protein expression represent a group of high grade B-cell lymphomas with inferior outcomes when treated with standard RCHOP chemotherapy. As a result, intensified induction regimens have been suggested in an effort to improve outcomes. Conclusions to date have largely been drawn from retrospective data although prospective data is slowly starting to emerge. Chemoimmunotherapy refractoriness is problematic and relapse rates are high...
September 30, 2016: Blood Reviews
Michel Varrin-Doyer, Kara L Pekarek, Collin M Spencer, Claude C A Bernard, Raymond A Sobel, Bruce A C Cree, Ulf Schulze-Topphoff, Scott S Zamvil
OBJECTIVE: To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55-specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgH(MOG-ki) [Th]) mice...
October 2016: Neurology® Neuroimmunology & Neuroinflammation
Mohammad O Hussaini, Friederike H Kreisel, Anjum Hassan, TuDung T Nguyen, John L Frater
CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case...
September 26, 2016: World Journal of Methodology
Li-Dan Zhao, Di Liang, Xiang-Ni Wu, Yang Li, Jing-Wen Niu, Chen Zhou, Li Wang, Hua Chen, Wen-Jie Zheng, Yun-Yun Fei, Fu-Lin Tang, Yong-Zhe Li, Feng-Chun Zhang, Wei He, Xue-Tao Cao, Xuan Zhang
Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected...
September 26, 2016: Cellular & Molecular Immunology
Marco Lucioni, Emilio Berti, Luca Arcaini, Giorgio A Croci, Aldo Maffi, Catherine Klersy, Gaia Goteri, Carlo Tomasini, Pietro Quaglino, Roberta Riboni, Mariarosa Arra, Elena Dallera, Vieri Grandi, Mauro Alaibac, Antonio Ramponi, Sara Rattotti, Maria Giuseppina Cabras, Silvia Franceschetti, Giulio Fraternali-Orcioni, Nicola Zerbinati, Francesco Onida, Stefano Ascani, Maria Teresa Fierro, Serena Rupoli, Marcello Gambacorta, Pier Luigi Zinzani, Nicola Pimpinelli, Marco Santucci, Marco Paulli
Categorization of primary cutaneous B-cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus-based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL...
September 26, 2016: Cancer Medicine
Karen L Bunting, T David Soong, Rajat Singh, Yanwen Jiang, Wendy Béguelin, David W Poloway, Brandon L Swed, Katerina Hatzi, William Reisacher, Matt Teater, Olivier Elemento, Ari M Melnick
During the humoral immune response, B cells undergo a dramatic change in phenotype to enable antibody affinity maturation in germinal centers (GCs). Using genome-wide chromosomal conformation capture (Hi-C), we found that GC B cells undergo massive reorganization of the genomic architecture that encodes the GC B cell transcriptome. Coordinate expression of genes that specify the GC B cell phenotype-most prominently BCL6-was achieved through a multilayered chromatin reorganization process involving (1) increased promoter connectivity, (2) formation of enhancer networks, (3) 5' to 3' gene looping, and (4) merging of gene neighborhoods that share active epigenetic marks...
September 20, 2016: Immunity
Jihyun Kim, Jeong-Ok Lee, Jin Ho Paik, Won Woo Lee, Sang Eun Kim, Yoo Sung Song
PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a pathologically heterogeneous disease with different prognoses according to its molecular profiles. Despite the broad usage of (18)F-fluoro-2-dexoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), previous studies that have investigated the value of interim (18)F-FDG PET/CT in DLBCL have given the controversial results. The purpose of this study was to evaluate the prognostic value of interim (18)F-FDG PET/CT in DLBCL according to germinal center B cell-like (GCB) and non-GCB molecular profiling...
September 15, 2016: Annals of Nuclear Medicine
Feng Shi, Quan Zhou, Ying Gao, Xiang-Qing Cui, Hong Chang
B-cell lymphoma (BCL), unclassifiable, with features intermediate between diffuse large BCL (DLBCL) and classical Hodgkin's lymphoma (CHL), is a novel entity to the World Health Organization classification system. These tumors are rare aggressive lymphomas that have a poor prognosis. The present study reports the case of a patient with one such lymphoma that occurred in the spleen, which expressed cluster of differentiation (CD)20, CD79α, melanoma associated antigen (mutated) 1, BCL6, CD15 and CD30. Polymerase chain reaction analysis demonstrated a clonal rearrangement of the genes coding for immunoglobulin heavy chains...
September 2016: Oncology Letters
Ana E Suárez, M J Artiga, Carlos Santonja, Santiago Montes-Moreno, P De Pablo, Luis Requena, Miguel A Piris, Socorro M Rodríguez-Pinilla
Plasma cell proliferations in specific cutaneous lesions of angioimmunoblastic T-cell lymphoma(AITL) are very uncommon. Here, we report a case of clonal plasma cell proliferation in skin with heavy-chain-immunoglobulin-isotype-switch after cutaneous disease progression. Histopathologically, initial plaque lesions were suggestive of marginal-zone B-cell-lymphoma. Nevertheless, this 77-year-old lady was diagnosed with AITL after the progression of skin lesions from plaques to nodular tumors. A lymph node biopsy confirmed the diagnosis...
September 6, 2016: Journal of Cutaneous Pathology
Pragya Rampuria, Gillian A Lang, T Scott Devera, Casey Gilmore, Jimmy D Ballard, Mark L Lang
Activation of iNKT cells with the CD1d-binding glycolipid adjuvant α-galactosylceramide (α-GC) enhances humoral immunity specific for coadministered T-dependent Ag. However, the relationship between the iNKT cell and the classic T helper (Th) or T follicular helper (Tfh) function following this immunization modality remains unclear. We show that immunization with the C-terminal domain (CTD) of Clostridium difficile toxin B (TcdB), accompanied by activation of iNKT cells with α-GC, led to enhanced production of CTD-specific IgG, which was CD1d- and iNKT cell-dependent and associated with increased neutralization of active TcdB...
August 26, 2016: Journal of Leukocyte Biology
Taishi Takahara, Keitaro Matsuo, Masao Seto, Shigeo Nakamura, Shinobu Tsuzuki
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center (GC) B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene-transduced GC B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, employing our lymphoma model...
August 25, 2016: Cancer Science
Vanessa Sue Wacleche, Jean-Philippe Goulet, Annie Gosselin, Patricia Monteiro, Hugo Soudeyns, Rémi Fromentin, Mohammad-Ali Jenabian, Shant Vartanian, Steven G Deeks, Nicolas Chomont, Jean-Pierre Routy, Petronela Ancuta
BACKGROUND: Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown. RESULTS: Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART...
2016: Retrovirology
Victor H Carpio, Michael M Opata, Marelle E Montañez, Pinaki P Banerjee, Alexander L Dent, Robin Stephens
[This corrects the article DOI: 10.1371/journal.pone.0144654.].
2016: PloS One
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