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https://www.readbyqxmd.com/read/27846392/a-druggable-tcf4-and-brd4-dependent-transcriptional-network-sustains-malignancy-in-blastic-plasmacytoid-dendritic-cell-neoplasm
#1
Michele Ceribelli, Zhiying Esther Hou, Priscilla N Kelly, Da Wei Huang, George Wright, Karthik Ganapathi, Moses O Evbuomwan, Stefania Pittaluga, Arthur L Shaffer, Guido Marcucci, Stephen J Forman, Wenming Xiao, Rajarshi Guha, Xiaohu Zhang, Marc Ferrer, Laurence Chaperot, Joel Plumas, Elaine S Jaffe, Craig J Thomas, Boris Reizis, Louis M Staudt
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27799566/epigenetic-gene-regulation-by-janus-kinase-1-in-diffuse-large-b-cell-lymphoma
#2
Lixin Rui, Amanda C Drennan, Michele Ceribelli, Fen Zhu, George W Wright, Da Wei Huang, Wenming Xiao, Yangguang Li, Kreg M Grindle, Li Lu, Daniel J Hodson, Arthur L Shaffer, Hong Zhao, Weihong Xu, Yandan Yang, Louis M Staudt
Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells...
October 31, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27551721/correction-type-2-diabetes-risk-allele-loci-in-the-qatari-population
#3
Sarah L O'Beirne, Jacqueline Salit, Juan L Rodriguez-Flores, Michelle R Staudt, Charbel Abi Khalil, Khalid A Fakhro, Amal Robay, Monica D Ramstetter, Iman K Al-Azwani, Joel A Malek, Mahmoud Zirie, Amin Jayyousi, Ramin Badii, Ajayeb Al-Nabet Al-Marri, Maria J Chiuchiolo, Alya Al-Shakaki, Omar Chidiac, Maey Gharbiah, Abdulbari Bener, Dora Stadler, Neil R Hackett, Jason G Mezey, Ronald G Crystal
[This corrects the article DOI: 10.1371/journal.pone.0156834.].
2016: PloS One
https://www.readbyqxmd.com/read/27408750/the-qatar-genome-a-population-specific-tool-for-precision-medicine-in-the-middle-east
#4
Khalid A Fakhro, Michelle R Staudt, Monica Denise Ramstetter, Amal Robay, Joel A Malek, Ramin Badii, Ajayeb Al-Nabet Al-Marri, Charbel Abi Khalil, Alya Al-Shakaki, Omar Chidiac, Dora Stadler, Mahmoud Zirie, Amin Jayyousi, Jacqueline Salit, Jason G Mezey, Ronald G Crystal, Juan L Rodriguez-Flores
Reaching the full potential of precision medicine depends on the quality of personalized genome interpretation. In order to facilitate precision medicine in regions of the Middle East and North Africa (MENA), a population-specific genome for the indigenous Arab population of Qatar (QTRG) was constructed by incorporating allele frequency data from sequencing of 1,161 Qataris, representing 0.4% of the population. A total of 20.9 million single nucleotide polymorphisms (SNPs) and 3.1 million indels were observed in Qatar, including an average of 1...
2016: Human Genome Variation
https://www.readbyqxmd.com/read/27389057/combined-copy-number-and-mutation-analysis-identifies-oncogenic-pathways-associated-with-transformation-of-follicular-lymphoma
#5
A Bouska, W Zhang, Q Gong, J Iqbal, A Scuto, J Vose, M Ludvigsen, K Fu, D D Weisenburger, T C Greiner, R D Gascoyne, A Rosenwald, G Ott, E Campo, L M Rimsza, J Delabie, E S Jaffe, R M Braziel, J M Connors, C-I Wu, L M Staudt, F D'Amore, T W McKeithan, W C Chan
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information...
July 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27383215/type-2-diabetes-risk-allele-loci-in-the-qatari-population
#6
Sarah L O'Beirne, Jacqueline Salit, Juan L Rodriguez-Flores, Michelle R Staudt, Charbel Abi Khalil, Khalid A Fakhro, Amal Robay, Monica D Ramstetter, Iman K Al-Azwani, Joel A Malek, Mahmoud Zirie, Amin Jayyousi, Ramin Badii, Ajayeb Al-Nabet Al-Marri, Maria J Chiuchiolo, Alya Al-Shakaki, Omar Chidiac, Maey Gharbiah, Abdulbari Bener, Dora Stadler, Neil R Hackett, Jason G Mezey, Ronald G Crystal
BACKGROUND: The prevalence of type 2 diabetes (T2D) is increasing in the Middle East. However, the genetic risk factors for T2D in the Middle Eastern populations are not known, as the majority of studies of genetic risk for T2D are in Europeans and Asians. METHODS: All subjects were ≥3 generation Qataris. Cases with T2D (n = 1,124) and controls (n = 590) were randomly recruited and assigned to the 3 known Qatari genetic subpopulations [Bedouin (Q1), Persian/South Asian (Q2) and African (Q3)]...
2016: PloS One
https://www.readbyqxmd.com/read/27316455/molecular-determinants-that-mediate-the-sorting-of-human-atg9a-from-the-endoplasmic-reticulum
#7
Catherine Staudt, Florentine Gilis, Marielle Boonen, Michel Jadot
ATG9A is a multispanning membrane protein required for autophagosome formation. Under basal conditions, neosynthesized ATG9A proteins travel to the Golgi apparatus and cycle between the trans-Golgi network and endosomes. In the present work, we searched for molecular determinants involved in the subcellular trafficking of human ATG9A in HeLa cells using sequential deletions and point mutations. Deletion of amino acids L(340) to L(354) resulted in the retention of ATG9A in the endoplasmic reticulum. In addition, we found that substitution of the L(711)YM(713) sequence (located in the C-terminal region of ATG9A) by alanine residues severely impaired its transport through the Golgi apparatus...
September 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27070702/targeting-non-proteolytic-protein-ubiquitination-for-the-treatment-of-diffuse-large-b-cell-lymphoma
#8
COMPARATIVE STUDY
Yibin Yang, Priscilla Kelly, Arthur L Shaffer, Roland Schmitz, Hee Min Yoo, Xinyue Liu, Da Wei Huang, Daniel Webster, Ryan M Young, Masao Nakagawa, Michele Ceribelli, George W Wright, Yandan Yang, Hong Zhao, Xin Yu, Weihong Xu, Wing C Chan, Elaine S Jaffe, Randy D Gascoyne, Elias Campo, Andreas Rosenwald, German Ott, Jan Delabie, Lisa Rimsza, Louis M Staudt
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation...
April 11, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27007171/pulmonary-abnormalities-in-young-light-use-waterpipe-hookah-smokers
#9
Yael Strulovici-Barel, Renat Shaykhiev, Jacqueline Salit, Ruba S Deeb, Anja Krause, Robert J Kaner, Thomas L Vincent, Francisco Agosto-Perez, Guoqing Wang, Charleen Hollmann, Vignesh Shanmugam, Ahmad M Almulla, Hisham Sattar, Mai Mahmoud, Jason G Mezey, Steven S Gross, Michelle R Staudt, Matthew S Walters, Ronald G Crystal
RATIONALE: Waterpipes, also called hookahs, are currently used by millions of people worldwide. Despite the increasing use of waterpipe smoking, there is limited data on the health effects of waterpipe smoking and there are no federal regulations regarding its use. OBJECTIVES: To assess the effects of waterpipe smoking on the human lung using clinical and biological parameters in young, light-use waterpipe smokers. METHODS: We assessed young, light-use, waterpipe-only smokers in comparison with lifelong nonsmokers using clinical parameters of cough and sputum scores, lung function, and chest high-resolution computed tomography as well as biological parameters of lung epithelial lining fluid metabolome, small airway epithelial (SAE) cell differential and transcriptome, alveolar macrophage transcriptome, and plasma apoptotic endothelial cell microparticles...
September 1, 2016: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/26993806/regulation-of-normal-b-cell-differentiation-and-malignant-b-cell-survival-by-oct2
#10
Daniel J Hodson, Arthur L Shaffer, Wenming Xiao, George W Wright, Roland Schmitz, James D Phelan, Yandan Yang, Daniel E Webster, Lixin Rui, Holger Kohlhammer, Masao Nakagawa, Thomas A Waldmann, Louis M Staudt
The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B...
April 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26820358/combination-of-forward-osmosis-fo-process%C3%A2-with-coagulation-flocculation-cf-for-potential-treatment-of-textile-wastewater
#11
Gang Han, Can-Zeng Liang, Tai-Shung Chung, Martin Weber, Claudia Staudt, Christian Maletzko
A novel combination of forward osmosis (FO) process with coagulation/flocculation (CF) (FO-CF) has been experimentally conceived for the treatment and reuse of textile wastewater. FO is employed to spontaneously recover water from the wastewater via osmosis and thus effectively reduces its volume with a dramatically enhanced dye concentration. CF is then applied to precipitate and remove dyes from the FO concentrated stream with much improved efficiency and reduced chemical dosage. The FO-CF hybrid system exhibits unique advantages of high water flux and recovery rate, well controlled membrane fouling, high efficiency, and minimal environmental impact...
March 15, 2016: Water Research
https://www.readbyqxmd.com/read/26787899/subtype-specific-addiction-of-the-activated-b-cell-subset-of-diffuse-large-b-cell-lymphoma-to-foxp1
#12
Joseph D Dekker, Daechan Park, Arthur L Shaffer, Holger Kohlhammer, Wei Deng, Bum-Kyu Lee, Gregory C Ippolito, George Georgiou, Vishwanath R Iyer, Louis M Staudt, Haley O Tucker
High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26785329/treadmill-measures-of-ambulation-rates-in-ovine-models-of-spinal-cord-injury-and-neuropathic-pain
#13
S Safayi, J W Miller, S Wilson, S K Shivapour, T F Oelfke, A L Ford, A Klarmann Staudt, K Abode-Iyamah, C G Reddy, N D Jeffery, D C Fredericks, G T Gillies, M A Howard
Our laboratories are developing treadmill-based gait analysis employing sheep to investigate potential efficacy of intra-dural spinal cord stimulation in the treatment of spinal cord injury and neuropathic pain. As part of efforts to establish the performance characteristics of the experimental arrangement, this study measured the treadmill speed via a tachometer, video belt-marker timing and ambulation-rate observations of the sheep. The data reveal a 0.1-0.3% residual drift in the baseline (unloaded) treadmill speed which increases with loading, but all three approaches agree on final speed to within 1...
2016: Journal of Medical Engineering & Technology
https://www.readbyqxmd.com/read/26719098/recurrent-activating-mutations-of-cd28-in-peripheral-t-cell-lymphomas
#14
J Rohr, S Guo, J Huo, A Bouska, C Lachel, Y Li, P D Simone, W Zhang, Q Gong, C Wang, A Cannon, T Heavican, A Mottok, S Hung, A Rosenwald, R Gascoyne, K Fu, T C Greiner, D D Weisenburger, J M Vose, L M Staudt, W Xiao, G E O Borgstahl, S Davis, C Steidl, T McKeithan, J Iqbal, W C Chan
Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation. We have identified recurrent mutations in CD28 in PTCLs...
May 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/26621451/selective-interleukin-1-receptor-associated-kinase-4-inhibitors-for-the-treatment-of-autoimmune-disorders-and-lymphoid-malignancy
#15
Priscilla N Kelly, Donna L Romero, Yibin Yang, Arthur L Shaffer, Divya Chaudhary, Shaughnessy Robinson, Wenyan Miao, Lixin Rui, William F Westlin, Rosana Kapeller, Louis M Staudt
Pathological activation of the Toll-like receptor signaling adaptor protein MYD88 underlies many autoimmune and inflammatory disease states. In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the oncogenic MYD88 L265P mutation occurs in 29% of cases, making it the most prevalent activating mutation in this malignancy. IRAK4 kinase accounts for almost all of the biological functions of MYD88, highlighting IRAK4 as a therapeutic target for diseases driven by aberrant MYD88 signaling...
December 14, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/26490036/copy-number-variations-in-the-genome-of-the-qatari-population
#16
Khalid A Fakhro, Noha A Yousri, Juan L Rodriguez-Flores, Amal Robay, Michelle R Staudt, Francisco Agosto-Perez, Jacqueline Salit, Joel A Malek, Karsten Suhre, Amin Jayyousi, Mahmoud Zirie, Dora Stadler, Jason G Mezey, Ronald G Crystal
BACKGROUND: The populations of the Arabian Peninsula remain the least represented in public genetic databases, both in terms of single nucleotide variants and of larger genomic mutations. We present the first high-resolution copy number variation (CNV) map for a Gulf Arab population, using a hybrid approach that integrates array genotyping intensity data and next-generation sequencing reads to call CNVs in the Qatari population. METHODS: CNVs were detected in 97 unrelated Qatari individuals by running two calling algorithms on each of two primary datasets: high-resolution genotyping (Illumina Omni 2...
October 22, 2015: BMC Genomics
https://www.readbyqxmd.com/read/26465791/growth-nutrition-and-cytokine-response-of-breast-fed-infants-and-infants-fed-formula-with-added-bovine-osteopontin
#17
Bo Lönnerdal, Anne S Kvistgaard, Janet M Peerson, Sharon M Donovan, Yong-mei Peng
OBJECTIVES: Breast milk contains a high concentration of osteopontin (OPN), a protein having multiple functions. In contrast, infant formula is low in OPN. A randomized clinical trial was performed to evaluate effects of adding a highly enriched bovine OPN fraction to formula, and infants whose mothers had already decided not to breast-feed were recruited. They were fed regular formula (F0) or the same formula with bovine OPN at 65 (F65) or 130 (F130) mg/L (50% and 100% of human milk level, respectively) from 1 to 6 months of age and were compared with a reference group of breast-fed (BF) infants...
April 2016: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/26231120/protein-tyrosine-phosphatase-ptprs-is-an-inhibitory-receptor-on-human-and-murine-plasmacytoid-dendritic-cells
#18
Anna Bunin, Vanja Sisirak, Hiyaa S Ghosh, Lucja T Grajkowska, Z Esther Hou, Michelle Miron, Cliff Yang, Michele Ceribelli, Noriko Uetani, Laurence Chaperot, Joel Plumas, Wiljan Hendriks, Michel L Tremblay, Hans Häcker, Louis M Staudt, Peter H Green, Govind Bhagat, Boris Reizis
Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS(-) pDCs produced IFN-α. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line...
August 18, 2015: Immunity
https://www.readbyqxmd.com/read/26193343/targeting-b-cell-receptor-signaling-with-ibrutinib-in-diffuse-large-b-cell-lymphoma
#19
Wyndham H Wilson, Ryan M Young, Roland Schmitz, Yandan Yang, Stefania Pittaluga, George Wright, Chih-Jian Lih, P Mickey Williams, Arthur L Shaffer, John Gerecitano, Sven de Vos, Andre Goy, Vaishalee P Kenkre, Paul M Barr, Kristie A Blum, Andrei Shustov, Ranjana Advani, Nathan H Fowler, Julie M Vose, Rebecca L Elstrom, Thomas M Habermann, Jacqueline C Barrientos, Jesse McGreivy, Maria Fardis, Betty Y Chang, Fong Clow, Brian Munneke, Davina Moussa, Darrin M Beaupre, Louis M Staudt
The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling...
August 2015: Nature Medicine
https://www.readbyqxmd.com/read/26078269/tick-salivary-sialostatin-l-represses-the-initiation-of-immune-responses-by-targeting-irf4-dependent-transcription-in-murine-mast-cells
#20
Matthias Klein, Till-Julius Brühl, Valérie Staudt, Sebastian Reuter, Nadine Grebe, Bastian Gerlitzki, Markus Hoffmann, Toszka Bohn, Alexander Ulges, Natascha Stergiou, Jos de Graaf, Martin Löwer, Christian Taube, Marc Becker, Tobias Hain, Sarah Dietzen, Michael Stassen, Magdalena Huber, Michael Lohoff, Andrezza Campos Chagas, John Andersen, Jan Kotál, Helena Langhansová, Jan Kopecký, Hansjörg Schild, Michalis Kotsyfakis, Edgar Schmitt, Tobias Bopp
Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells...
July 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
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