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Riccardo Dalla-Favera

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https://www.readbyqxmd.com/read/27166359/fbxo11-inactivation-leads-to-abnormal-germinal-center-formation-and-lymphoproliferative-disease
#1
Christof Schneider, Ning Kon, Letizia Amadori, Qiong Shen, Friederike H Schwartz, Benjamin Tischler, Marion Bossennec, David Dominguez-Sola, Govind Bhagat, Wei Gu, Katia Basso, Riccardo Dalla-Favera
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for the germinal center (GC) reaction and is implicated in lymphomagenesis. BCL6 protein stability is regulated by F-box protein 11 (FBXO11)-mediated ubiquitination and degradation, which is impaired in ∼6% of diffuse large B-cell lymphomas that carry inactivating genetic alterations targeting the FBXO11 gene. In order to investigate the role of FBXO11 in vivo, we analyzed GC-specific FBXO11 knockout mice. FBXO11 reduction or loss led to an increased number of GC B cells, to an altered ratio of GC dark zone to light zone cells, and to higher levels of BCL6 protein in GC B cells...
August 4, 2016: Blood
https://www.readbyqxmd.com/read/27030389/genetic-basis-of-pd-l1-overexpression-in-diffuse-large-b-cell-lymphomas
#2
Konstantinos Georgiou, Longyun Chen, Mattias Berglund, Weicheng Ren, Noel F C C de Miranda, Susana Lisboa, Marco Fangazio, Shida Zhu, Yong Hou, Kui Wu, Wenfeng Fang, Xianhuo Wang, Bin Meng, Li Zhang, Yixin Zeng, Govind Bhagat, Magnus Nordenskjöld, Christer Sundström, Gunilla Enblad, Riccardo Dalla-Favera, Huilai Zhang, Manuel R Teixeira, Laura Pasqualucci, Roujun Peng, Qiang Pan-Hammarström
Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort...
June 16, 2016: Blood
https://www.readbyqxmd.com/read/26911189/the-molecular-pathogenesis-of-chronic-lymphocytic-leukaemia
#3
REVIEW
Giulia Fabbri, Riccardo Dalla-Favera
Recent investigations have provided an increasingly complete picture of the genetic landscape of chronic lymphocytic leukaemia (CLL). These analyses revealed that the CLL genome displays a high degree of heterogeneity between patients and within the same patient. In addition, they highlighted molecular mechanisms and functionally relevant biological programmes that may be important for the pathogenesis and therapeutic targeting of this disease. This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of CLL...
March 2016: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/26620759/the-foxo1-transcription-factor-instructs-the-germinal-center-dark-zone-program
#4
David Dominguez-Sola, Jennifer Kung, Antony B Holmes, Victoria A Wells, Tongwei Mo, Katia Basso, Riccardo Dalla-Favera
The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation...
December 15, 2015: Immunity
https://www.readbyqxmd.com/read/26366712/disruption-of-kmt2d-perturbs-germinal-center-b-cell-development-and-promotes-lymphomagenesis
#5
Jiyuan Zhang, David Dominguez-Sola, Shafinaz Hussein, Ji-Eun Lee, Antony B Holmes, Mukesh Bansal, Sofija Vlasevska, Tongwei Mo, Hongyan Tang, Katia Basso, Kai Ge, Riccardo Dalla-Favera, Laura Pasqualucci
Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice...
October 2015: Nature Medicine
https://www.readbyqxmd.com/read/25921526/an-oncogenic-role-for-alternative-nf-%C3%AE%C2%BAb-signaling-in-dlbcl-revealed-upon-deregulated-bcl6-expression
#6
Baochun Zhang, Dinis Pedro Calado, Zhe Wang, Sebastian Fröhler, Karl Köchert, Yu Qian, Sergei B Koralov, Marc Schmidt-Supprian, Yoshiteru Sasaki, Christine Unitt, Scott Rodig, Wei Chen, Riccardo Dalla-Favera, Frederick W Alt, Laura Pasqualucci, Klaus Rajewsky
Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation...
May 5, 2015: Cell Reports
https://www.readbyqxmd.com/read/25805586/the-genetic-landscape-of-diffuse-large-b-cell-lymphoma
#7
REVIEW
Laura Pasqualucci, Riccardo Dalla-Favera
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in the western world, is an aggressive disease that remains incurable in approximately 30% of patients. Over the past decade, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic and transcriptional changes has revolutionized our understanding of the genetic basis of DLBCL by providing a comprehensive and unbiased view of the genes/pathways that are disrupted by genetic alterations in this disease, and may contribute to tumor initiation and expansion...
April 2015: Seminars in Hematology
https://www.readbyqxmd.com/read/25712152/germinal-centres-and-b-cell-lymphomagenesis
#8
REVIEW
Katia Basso, Riccardo Dalla-Favera
Germinal centres (GCs) are involved in the selection of B cells secreting high-affinity antibodies and are also the origin of most human B cell lymphomas. Recent progress has been made in identifying the functionally relevant stages of the GC and the complex trafficking mechanisms of B cells within the GC. These studies have identified transcription factors and signalling pathways that regulate distinct phases of GC development. Notably, these factors and pathways are hijacked during tumorigenesis, as revealed by analyses of the genetic lesions associated with various types of B cell lymphomas...
March 2015: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/25083870/genome-wide-mapping-and-characterization-of-notch-regulated-long-noncoding-rnas-in-acute-leukemia
#9
Thomas Trimarchi, Erhan Bilal, Panagiotis Ntziachristos, Giulia Fabbri, Riccardo Dalla-Favera, Aristotelis Tsirigos, Iannis Aifantis
Notch signaling is a key developmental pathway that is subject to frequent genetic and epigenetic perturbations in many different human tumors. Here we investigate whether long noncoding RNA (lncRNA) genes, in addition to mRNAs, are key downstream targets of oncogenic Notch1 in human T cell acute lymphoblastic leukemia (T-ALL). By integrating transcriptome profiles with chromatin state maps, we have uncovered many previously unreported T-ALL-specific lncRNA genes, a fraction of which are directly controlled by the Notch1/Rpbjκ activator complex...
July 31, 2014: Cell
https://www.readbyqxmd.com/read/24843176/microrna-28-controls-cell-proliferation-and-is-down-regulated-in-b-cell-lymphomas
#10
Christof Schneider, Manu Setty, Antony B Holmes, Roy L Maute, Christina S Leslie, Lara Mussolin, Angelo Rosolen, Riccardo Dalla-Favera, Katia Basso
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating v-myc avian myelocytomatosis viral oncogene homolog (MYC). A comparative analysis of microRNAs expressed in normal and malignant GC B cells identified microRNA 28 (miR-28) as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that reexpression of miR-28 impairs cell proliferation and clonogenic properties of BL cells by modulating several targets including MAD2 mitotic arrest deficient-like 1, MAD2L1, a component of the spindle checkpoint whose down-regulation is essential in mediating miR-28-induced proliferation arrest, and BCL2-associated athanogene, BAG1, an activator of the ERK pathway...
June 3, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24550227/genetic-lesions-associated-with-chronic-lymphocytic-leukemia-chemo-refractoriness
#11
Monica Messina, Ilaria Del Giudice, Hossein Khiabanian, Davide Rossi, Sabina Chiaretti, Silvia Rasi, Valeria Spina, Antony B Holmes, Marilisa Marinelli, Giulia Fabbri, Alfonso Piciocchi, Francesca R Mauro, Anna Guarini, Gianluca Gaidano, Riccardo Dalla-Favera, Laura Pasqualucci, Raul Rabadan, Robin Foà
Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ~70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27...
April 10, 2014: Blood
https://www.readbyqxmd.com/read/24434215/snapshot-diffuse-large-b-cell-lymphoma
#12
REVIEW
Laura Pasqualucci, Riccardo Dalla-Favera
No abstract text is available yet for this article.
January 13, 2014: Cancer Cell
https://www.readbyqxmd.com/read/24388756/genetics-of-follicular-lymphoma-transformation
#13
Laura Pasqualucci, Hossein Khiabanian, Marco Fangazio, Mansi Vasishtha, Monica Messina, Antony B Holmes, Peter Ouillette, Vladimir Trifonov, Davide Rossi, Fabrizio Tabbò, Maurilio Ponzoni, Amy Chadburn, Vundavalli V Murty, Govind Bhagat, Gianluca Gaidano, Giorgio Inghirami, Sami N Malek, Raul Rabadan, Riccardo Dalla-Favera
Follicular lymphoma (FL) is an indolent disease, but 30%-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation...
January 16, 2014: Cell Reports
https://www.readbyqxmd.com/read/24127483/genetic-lesions-associated-with-chronic-lymphocytic-leukemia-transformation-to-richter-syndrome
#14
Giulia Fabbri, Hossein Khiabanian, Antony B Holmes, Jiguang Wang, Monica Messina, Charles G Mullighan, Laura Pasqualucci, Raul Rabadan, Riccardo Dalla-Favera
Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case...
October 21, 2013: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/24039180/rnas-with-multiple-personalities
#15
REVIEW
Roy L Maute, Riccardo Dalla-Favera, Katia Basso
In the last decade, advances in sequencing technology and a renewed focus on the regulatory potential of RNA molecules have combined to stimulate an enormous expansion in the catalog of known eukaryotic RNAs. Beyond the sheer numerical diversity of RNA species, recent studies have begun to uncover hints of even greater functional complexity. An increasing number of RNA molecules, including those from classic, well-studied classes, have been found to act in previously unanticipated regulatory roles, or as substrate for the biogenesis of functionally distinct RNA molecules, or both...
January 2014: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/23974956/mef2b-mutations-lead-to-deregulated-expression-of-the-oncogene-bcl6-in-diffuse-large-b-cell-lymphoma
#16
Carol Y Ying, David Dominguez-Sola, Melissa Fabi, Ivo C Lorenz, Shafinaz Hussein, Mukesh Bansal, Andrea Califano, Laura Pasqualucci, Katia Basso, Riccardo Dalla-Favera
MEF2B encodes a transcriptional activator and is mutated in ∼11% of diffuse large B cell lymphomas (DLBCLs) and ∼12% of follicular lymphomas (FLs). Here we found that MEF2B directly activated the transcription of the proto-oncogene BCL6 in normal germinal-center (GC) B cells and was required for DLBCL proliferation. Mutation of MEF2B resulted in enhanced transcriptional activity of MEF2B either through disruption of its interaction with the corepressor CABIN1 or by rendering it insensitive to inhibitory signaling events mediated by phosphorylation and sumoylation...
October 2013: Nature Immunology
https://www.readbyqxmd.com/read/23531283/mutcomfocal-an-integrative-approach-to-identifying-recurrent-and-focal-genomic-alterations-in-tumor-samples
#17
Vladimir Trifonov, Laura Pasqualucci, Riccardo Dalla Favera, Raul Rabadan
BACKGROUND: Most tumors are the result of accumulated genomic alterations in somatic cells. The emerging spectrum of alterations in tumors is complex and the identification of relevant genes and pathways remains a challenge. Furthermore, key cancer genes are usually found amplified or deleted in chromosomal regions containing many other genes. Point mutations, on the other hand, provide exquisite information about amino acid changes that could be implicated in the oncogenic process. Current large-scale genomic projects provide high throughput genomic data in a large number of well-characterized tumor samples...
2013: BMC Systems Biology
https://www.readbyqxmd.com/read/23297232/trna-derived-microrna-modulates-proliferation-and-the-dna-damage-response-and-is-down-regulated-in-b-cell-lymphoma
#18
Roy L Maute, Christof Schneider, Pavel Sumazin, Antony Holmes, Andrea Califano, Katia Basso, Riccardo Dalla-Favera
Sequencing studies from several model systems have suggested that diverse and abundant small RNAs may be derived from tRNA, but the function of these molecules remains undefined. Here, we demonstrate that one such tRNA-derived fragment, cloned from human mature B cells and designated CU1276, in fact possesses the functional characteristics of a microRNA, including a DICER1-dependent biogenesis, physical association with Argonaute proteins, and the ability to repress mRNA transcripts in a sequence-specific manner...
January 22, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/23243274/integrated-mutational-and-cytogenetic-analysis-identifies-new-prognostic-subgroups-in-chronic-lymphocytic-leukemia
#19
Davide Rossi, Silvia Rasi, Valeria Spina, Alessio Bruscaggin, Sara Monti, Carmela Ciardullo, Clara Deambrogi, Hossein Khiabanian, Roberto Serra, Francesco Bertoni, Francesco Forconi, Luca Laurenti, Roberto Marasca, Michele Dal-Bo, Francesca Maria Rossi, Pietro Bulian, Josep Nomdedeu, Giovanni Del Poeta, Valter Gattei, Laura Pasqualucci, Raul Rabadan, Robin Foà, Riccardo Dalla-Favera, Gianluca Gaidano
The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69...
February 21, 2013: Blood
https://www.readbyqxmd.com/read/23166356/bcl6-positively-regulates-aid-and-germinal-center-gene-expression-via-repression-of-mir-155
#20
Katia Basso, Christof Schneider, Qiong Shen, Antony B Holmes, Manu Setty, Christina Leslie, Riccardo Dalla-Favera
The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose de-regulation is involved in lymphomagenesis. Although substantial evidence indicates that BCL6 exerts its function by repressing the transcription of hundreds of protein-coding genes, its potential role in regulating gene expression via microRNAs (miRNAs) is not known. We have identified a core of 15 miRNAs that show binding of BCL6 in their genomic loci and are down-regulated in GC B cells...
December 17, 2012: Journal of Experimental Medicine
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