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2. Accelerated epigenetic aging in newborns with Down syndrome

Author

Xu, Keren, Li, Shaobo, Muskens, Ivo S, Elliott, Natalina, Myint, Swe Swe, Pandey, Priyatama, Hansen, Helen M, Morimoto, Libby M, Kang, Alice Y, Ma, Xiaomei, Metayer, Catherine, Mueller, Beth A, Roberts, Irene, Walsh, Kyle M, Horvath, Steve, Wiemels, Joseph L, and de Smith, Adam J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Intellectual and Developmental Disabilities (IDD), Aging, Brain Disorders, Down Syndrome, Congenital, Good Health and Well Being, Adult, Aging, Premature, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Infant, Newborn, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p

Published
2022

3. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

Author

Khoury, Joseph D, Solary, Eric, Abla, Oussama, Akkari, Yassmine, Alaggio, Rita, Apperley, Jane F, Bejar, Rafael, Berti, Emilio, Busque, Lambert, Chan, John KC, Chen, Weina, Chen, Xueyan, Chng, Wee-Joo, Choi, John K, Colmenero, Isabel, Coupland, Sarah E, Cross, Nicholas CP, De Jong, Daphne, Elghetany, M Tarek, Takahashi, Emiko, Emile, Jean-Francois, Ferry, Judith, Fogelstrand, Linda, Fontenay, Michaela, Germing, Ulrich, Gujral, Sumeet, Haferlach, Torsten, Harrison, Claire, Hodge, Jennelle C, Hu, Shimin, Jansen, Joop H, Kanagal-Shamanna, Rashmi, Kantarjian, Hagop M, Kratz, Christian P, Li, Xiao-Qiu, Lim, Megan S, Loeb, Keith, Loghavi, Sanam, Marcogliese, Andrea, Meshinchi, Soheil, Michaels, Phillip, Naresh, Kikkeri N, Natkunam, Yasodha, Nejati, Reza, Ott, German, Padron, Eric, Patel, Keyur P, Patkar, Nikhil, Picarsic, Jennifer, Platzbecker, Uwe, Roberts, Irene, Schuh, Anna, Sewell, William, Siebert, Reiner, Tembhare, Prashant, Tyner, Jeffrey, Verstovsek, Srdan, Wang, Wei, Wood, Brent, Xiao, Wenbin, Yeung, Cecilia, and Hochhaus, Andreas

Subjects
Genetics, Human Genome, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Hematologic Neoplasms, Histiocytosis, Humans, World Health Organization, Clinical Sciences, Oncology and Carcinogenesis, Immunology
Abstract

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Published
2022

5. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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6. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia

Author

Crump, Nicholas T., Smith, Alastair L., Godfrey, Laura, Dopico-Fernandez, Ana M., Denny, Nicholas, Harman, Joe R., Hamley, Joseph C., Jackson, Nicole E., Chahrour, Catherine, Riva, Simone, Rice, Siobhan, Kim, Jaehoon, Basrur, Venkatesha, Fermin, Damian, Elenitoba-Johnson, Kojo, Roeder, Robert G., Allis, C. David, Roberts, Irene, Roy, Anindita, Geng, Huimin, Davies, James O. J., and Milne, Thomas A.

Published
2023
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7. The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Author

Muskens, Ivo S, Li, Shaobo, Jackson, Thomas, Elliot, Natalina, Hansen, Helen M, Myint, Swe Swe, Pandey, Priyatama, Schraw, Jeremy M, Roy, Ritu, Anguiano, Joaquin, Goudevenou, Katerina, Siegmund, Kimberly D, Lupo, Philip J, de Bruijn, Marella FTR, Walsh, Kyle M, Vyas, Paresh, Ma, Xiaomei, Roy, Anindita, Roberts, Irene, Wiemels, Joseph L, and de Smith, Adam J

Subjects
Liver, Hematopoietic Stem Cells, Fetus, Humans, Down Syndrome, Case-Control Studies, Hematopoiesis, DNA Methylation, Epigenesis, Genetic, CpG Islands, Genome, Human, Infant, Newborn, Female, Male, Core Binding Factor Alpha 2 Subunit, GATA1 Transcription Factor, Proto-Oncogene Protein c-fli-1, Promoter Regions, Genetic, Genome-Wide Association Study, Epigenesis, Genetic, Genome, Human, Infant, Newborn, Promoter Regions
Abstract

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P

Published
2021

8. H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Author

Godfrey, Laura, Crump, Nicholas T, O’Byrne, Sorcha, Lau, I-Jun, Rice, Siobhan, Harman, Joe R, Jackson, Thomas, Elliott, Natalina, Buck, Gemma, Connor, Christopher, Thorne, Ross, Knapp, David JHF, Heidenreich, Olaf, Vyas, Paresh, Menendez, Pablo, Inglott, Sarah, Ancliff, Philip, Geng, Huimin, Roberts, Irene, Roy, Anindita, and Milne, Thomas A

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Orphan Drug, Hematology, Pediatric Cancer, Stem Cell Research - Nonembryonic - Non-Human, Rare Diseases, Stem Cell Research, Cancer, Pediatric, Genetics, Aetiology, 2.1 Biological and endogenous factors, AC133 Antigen, Biomarkers, Tumor, Cell Line, Tumor, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, Gene Silencing, Histones, Humans, Immunophenotyping, Leukemia, Models, Biological, Myeloid-Lymphoid Leukemia Protein, Neoplastic Stem Cells, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Protein Binding, Immunology, Cardiovascular medicine and haematology, Clinical sciences, Oncology and carcinogenesis
Abstract

MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

Published
2021

9. Germline variants in predisposition genes in children with Down syndrome and acute lymphoblastic leukemia

Author

Winer, Peleg, Muskens, Ivo S, Walsh, Kyle M, Vora, Ajay, Moorman, Anthony V, Wiemels, Joseph L, Roberts, Irene, Roy, Anindita, and de Smith, Adam J

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Child, Down Syndrome, Germ Cells, Germ-Line Mutation, Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Cardiovascular medicine and haematology
Abstract

Rare and pathogenic germline variants, including in IKZF1, contribute to acute lymphoblastic leukemia in children with Down syndrome.

Published
2020

10. CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies

Author

Bueno, Clara, Barrera, Susana, Bataller, Alex, Ortiz-Maldonado, Valentín, Elliot, Natalina, O'Byrne, Sorcha, Wang, Guanlin, Rovira, Montse, Gutierrez-Agüera, Francisco, Trincado, Juan L., González-González, María, Morgades, Mireia, Sorigué, Marc, Bárcena, Paloma, Zanetti, Samanta Romina, Torrebadell, Montse, Vega-Garcia, Nerea, Rives, Susana, Mallo, Mar, Sole, Francesc, Mead, Adam J., Roberts, Irene, Thongjuea, Supat, Psaila, Bethan, Juan, Manel, Delgado, Julio, Urbano-Ispizúa, Alvaro, Ribera, Josep María, Orfao, Alberto, Roy, Anindita, and Menendez, Pablo

Published
2022
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11. Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Author

Trasanidis, Nikolaos, Katsarou, Alexia, Ponnusamy, Kanagaraju, Shen, Yao-An, Kostopoulos, Ioannis V., Bergonia, Bien, Keren, Keren, Reema, Paudel, Xiao, Xiaolin, Szydlo, Richard M., Sabbattini, Pierangela M.R., Roberts, Irene A.G., Auner, Holger W., Naresh, Kikkeri N., Chaidos, Aristeidis, Wang, Tian-Li, Magnani, Luca, Caputo, Valentina S., and Karadimitris, Anastasios

Published
2022
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13. Blood and immune development in human fetal bone marrow and Down syndrome

Author

Jardine, Laura, Webb, Simone, Goh, Issac, Quiroga Londoño, Mariana, Reynolds, Gary, Mather, Michael, Olabi, Bayanne, Stephenson, Emily, Botting, Rachel A., Horsfall, Dave, Engelbert, Justin, Maunder, Daniel, Mende, Nicole, Murnane, Caitlin, Dann, Emma, McGrath, Jim, King, Hamish, Kucinski, Iwo, Queen, Rachel, Carey, Christopher D., Shrubsole, Caroline, Poyner, Elizabeth, Acres, Meghan, Jones, Claire, Ness, Thomas, Coulthard, Rowen, Elliott, Natalina, O’Byrne, Sorcha, Haltalli, Myriam L. R., Lawrence, John E., Lisgo, Steven, Balogh, Petra, Meyer, Kerstin B., Prigmore, Elena, Ambridge, Kirsty, Jain, Mika Sarkin, Efremova, Mirjana, Pickard, Keir, Creasey, Thomas, Bacardit, Jaume, Henderson, Deborah, Coxhead, Jonathan, Filby, Andrew, Hussain, Rafiqul, Dixon, David, McDonald, David, Popescu, Dorin-Mirel, Kowalczyk, Monika S., Li, Bo, Ashenberg, Orr, Tabaka, Marcin, Dionne, Danielle, Tickle, Timothy L., Slyper, Michal, Rozenblatt-Rosen, Orit, Regev, Aviv, Behjati, Sam, Laurenti, Elisa, Wilson, Nicola K., Roy, Anindita, Göttgens, Berthold, Roberts, Irene, Teichmann, Sarah A., and Haniffa, Muzlifah

Published
2021
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14. A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program

Author

Rice, Siobhan, Jackson, Thomas, Crump, Nicholas T., Fordham, Nicholas, Elliott, Natalina, O’Byrne, Sorcha, Fanego, Maria del Mar Lara, Addy, Dilys, Crabb, Trisevgeni, Dryden, Carryl, Inglott, Sarah, Ladon, Dariusz, Wright, Gary, Bartram, Jack, Ancliff, Philip, Mead, Adam J., Halsey, Christina, Roberts, Irene, Milne, Thomas A., and Roy, Anindita

Published
2021
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16. Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs

Author

O'Byrne, Sorcha, Elliott, Natalina, Rice, Siobhan, Buck, Gemma, Fordham, Nicholas, Garnett, Catherine, Godfrey, Laura, Crump, Nicholas T., Wright, Gary, Inglott, Sarah, Hua, Peng, Psaila, Bethan, Povinelli, Benjamin, Knapp, David J.H.F., Agraz-Doblas, Antonio, Bueno, Clara, Varela, Ignacio, Bennett, Phillip, Koohy, Hashem, Watt, Suzanne M., Karadimitris, Anastasios, Mead, Adam J., Ancliff, Phillip, Vyas, Paresh, Menendez, Pablo, Milne, Thomas A., Roberts, Irene, and Roy, Anindita

Published
2019
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17. Neonatal Leukemia

Author

Guest, Erin M., primary, Garnett, Catherine, additional, Roberts, Irene, additional, and Gamis, Alan S., additional

Published
2021
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21. Decoding human fetal liver haematopoiesis

Author

Popescu, Dorin-Mirel, Botting, Rachel A., Stephenson, Emily, Green, Kile, Webb, Simone, Jardine, Laura, Calderbank, Emily F., Polanski, Krzysztof, Goh, Issac, Efremova, Mirjana, Acres, Meghan, Maunder, Daniel, Vegh, Peter, Gitton, Yorick, Park, Jong-Eun, Vento-Tormo, Roser, Miao, Zhichao, Dixon, David, Rowell, Rachel, McDonald, David, Fletcher, James, Poyner, Elizabeth, Reynolds, Gary, Mather, Michael, Moldovan, Corina, Mamanova, Lira, Greig, Frankie, Young, Matthew D., Meyer, Kerstin B., Lisgo, Steven, Bacardit, Jaume, Fuller, Andrew, Millar, Ben, Innes, Barbara, Lindsay, Susan, Stubbington, Michael J. T., Kowalczyk, Monika S., Li, Bo, Ashenberg, Orr, Tabaka, Marcin, Dionne, Danielle, Tickle, Timothy L., Slyper, Michal, Rozenblatt-Rosen, Orit, Filby, Andrew, Carey, Peter, Villani, Alexandra-Chloé, Roy, Anindita, Regev, Aviv, Chédotal, Alain, Roberts, Irene, Göttgens, Berthold, Behjati, Sam, Laurenti, Elisa, Teichmann, Sarah A., and Haniffa, Muzlifah

Published
2019
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22. Yolk sac cell atlas reveals multiorgan functions during human early development

Author

Goh, Issac, primary, Botting, Rachel A., additional, Rose, Antony, additional, Webb, Simone, additional, Engelbert, Justin, additional, Gitton, Yorick, additional, Stephenson, Emily, additional, Quiroga Londoño, Mariana, additional, Mather, Michael, additional, Mende, Nicole, additional, Imaz-Rosshandler, Ivan, additional, Yang, Lu, additional, Horsfall, Dave, additional, Basurto-Lozada, Daniela, additional, Chipampe, Nana-Jane, additional, Rook, Victoria, additional, Lee, Jimmy Tsz Hang, additional, Ton, Mai-Linh, additional, Keitley, Daniel, additional, Mazin, Pavel, additional, Vijayabaskar, M. S., additional, Hannah, Rebecca, additional, Gambardella, Laure, additional, Green, Kile, additional, Ballereau, Stephane, additional, Inoue, Megumi, additional, Tuck, Elizabeth, additional, Lorenzi, Valentina, additional, Kwakwa, Kwasi, additional, Alsinet, Clara, additional, Olabi, Bayanne, additional, Miah, Mohi, additional, Admane, Chloe, additional, Popescu, Dorin-Mirel, additional, Acres, Meghan, additional, Dixon, David, additional, Ness, Thomas, additional, Coulthard, Rowen, additional, Lisgo, Steven, additional, Henderson, Deborah J., additional, Dann, Emma, additional, Suo, Chenqu, additional, Kinston, Sarah J., additional, Park, Jong-eun, additional, Polanski, Krzysztof, additional, Marioni, John, additional, van Dongen, Stijn, additional, Meyer, Kerstin B., additional, de Bruijn, Marella, additional, Palis, James, additional, Behjati, Sam, additional, Laurenti, Elisa, additional, Wilson, Nicola K., additional, Vento-Tormo, Roser, additional, Chédotal, Alain, additional, Bayraktar, Omer, additional, Roberts, Irene, additional, Jardine, Laura, additional, Göttgens, Berthold, additional, Teichmann, Sarah A., additional, and Haniffa, Muzlifah, additional

Published
2023
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23. P332: LIN28B: AN IMPORTANT ONCO-FETAL GENE IN INFANT ACUTE LYMPHOBLASTIC LEUKAEMIA

Author

Ling, Rebecca, primary, Jackson, Thomas, additional, Elliott, Natalina, additional, Cross, Joe, additional, Rice, Siobhan, additional, Howitt, Rebecca, additional, Smith, Alastair, additional, Harman, Joe, additional, T Crump, Nicholas, additional, Wang, Guanlin, additional, Iskander, Deena, additional, Thongjuea, Supat, additional, Ancliff, Philip, additional, Psaila, Beth, additional, Roberts, Irene, additional, Milne, Thomas, additional, and Roy, Anindita, additional

Published
2023
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25. Contributors

Author

Alsousou, Joseph, primary, Angiolillo, Dominick J., additional, Arachiche, Amal, additional, Aster, Richard H., additional, Barbui, Tiziano, additional, Basili, Stefania, additional, Battinelli, Elisabeth M., additional, Bavry, Anthony A., additional, Bergmeier, Wolfgang, additional, Bertrand, Gerald, additional, Bhatt, Deepak L., additional, Blair, Thomas A., additional, Bledzka, Kamila, additional, Borst, Oliver, additional, Bouck, Emma G., additional, Brass, Lawrence F., additional, Bray, Paul F., additional, Briggs, Carol, additional, Brzoska, Tomasz, additional, Bussel, James B., additional, Cattaneo, Marco, additional, Chakravorty, Subarna, additional, Chan, Noel C., additional, Chaturvedi, Shruti, additional, Chong, Beng H., additional, Clemetson, Kenneth J., additional, Clemetson, Jeannine M., additional, Coller, Barry S., additional, del Zoppo, Gregory J., additional, Despotovic, Jenny M., additional, Diamond, Scott L., additional, Easton, J. Donald, additional, Eto, Koji, additional, Falet, Hervé, additional, Ferrer-Marin, Francisca, additional, Finazzi, Guido, additional, Flaumenhaft, Robert, additional, Freedman, Jane E., additional, Frelinger, Andrew L., additional, Freson, Kathleen, additional, Gasecka, Aleksandra, additional, Gawaz, Meinrad, additional, Giannini, Silvia, additional, Greinacher, Andreas, additional, Gremmel, Thomas, additional, Gurbel, Paul A., additional, Haining, Elizabeth J., additional, Han, Xu, additional, Harrison, Paul, additional, Hayward, Catherine P.M., additional, Hoffmeister, Karin, additional, Hvas, Anne-Mette, additional, Israels, Sara J., additional, Italiano, Joseph E., additional, Jeong, Young-Hoon, additional, Johnson, Andrew D., additional, Kaplan, Cecile, additional, Karagiannis, Peter, additional, Kato, Gregory J., additional, Kemble, Samuel, additional, Kolandaivelu, Kumaran, additional, Koupenova, Milka, additional, Kuter, David J., additional, Lambert, Michele P., additional, Lee, Robert H., additional, Levin, Jack, additional, Li, Renhao, additional, Li, Zhenyu, additional, Li, Zihai, additional, Li, Anqi, additional, Liani, Rossella, additional, Lordkipanidzé, Marie, additional, Lorenz, Viola, additional, Machlus, Kellie R., additional, Mahtta, Dhruv, additional, Mannucci, Pier Mannuccio, additional, McCrae, Keith R., additional, Metelli, Alessandra, additional, Michelson, Alan D., additional, Moffat, Karen A., additional, Moon, Jae Youn, additional, Morrissey, James H., additional, Mutch, Nicola J., additional, Nagy, Zoltan, additional, Ni, Heyu, additional, Nicolson, Phillip L.R., additional, Nieman, Marvin T., additional, Nieuwland, Rienk, additional, Onselaer, Marie-Blanche, additional, Patrono, Carlo, additional, Plow, Edward F., additional, Poncz, Mortimer, additional, Poon, Man-Chiu, additional, Poulter, Natalie S., additional, Poventud-Fuentes, Izmarie, additional, Provost, Patrick, additional, Qin, Jun, additional, Rayes, Julie, additional, Reiner, Alexander P., additional, Riesenberg, Brian, additional, Roberts, Irene A.G., additional, Rondina, Matthew T., additional, Rowley, Jesse W., additional, Santilli, Francesca, additional, Scharf, Rüdiger E., additional, Senis, Yotis A., additional, Sharda, Anish, additional, Siddon, Alexa J., additional, Siljander, Pia R.-M., additional, Tricoci, Pierluigi, additional, Simeone, Paola, additional, Smith, Stephanie A., additional, Smyth, Susan S., additional, Snyder, Edward L., additional, Sola-Visner, Martha, additional, Stalker, Timothy J., additional, Stefanini, Lucia, additional, Sugimoto, Naoshi, additional, Sundd, Prithu, additional, Tantry, Udaya S., additional, Tefferi, Ayalew, additional, Thomas, Steven G., additional, Thomas, Mark R., additional, Tomaiuolo, Maurizio, additional, Tormey, Christopher A., additional, Tsai, Han-Mou, additional, Violi, Francesco, additional, Warkentin, Theodore E., additional, Watson, Steve P., additional, Weitz, Jeffrey I., additional, Welsh, John, additional, Weyrich, Andrew S., additional, Wilcox, David A., additional, Wu, Bill X., additional, Yeaman, Michael R., additional, Zhu, Li, additional, Zimmerman, Guy A., additional, and Zunica, Elizabeth R., additional

Published
2019
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29. Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation

Author

Chennupati, Vijaykumar, Veiga, Diogo F.T., Maslowski, Kendle M., Andina, Nicola, Tardivel, Aubry, Yu, Eric Chi-Wang, Stilinovic, Martina, Simillion, Cedric, Duchosal, Michel A., Quadroni, Manfredo, Roberts, Irene, Sankaran, Vijay G., MacDonald, H. Robson, Fasel, Nicolas, Angelillo-Scherrer, Anne, Schneider, Pascal, Hoang, Trang, and Allam, Ramanjaneyulu

Subjects
Embryonic development -- Physiological aspects -- Genetic aspects -- Research, Ribosomal proteins -- Physiological aspects -- Genetic aspects -- Research, Erythropoiesis -- Physiological aspects -- Genetic aspects -- Research, Gene expression -- Physiological aspects -- Research, Health care industry
Abstract

Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anemia and [5q.sup.-] syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal- associated factors in this process. Ribonuclease inhibitor 1 (RNH1) is a ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases. Here, we report that RNH1 binds to ribosomes and regulates erythropoiesis by controlling translation of the erythroid transcription factor GATA1. Rnh1- deficient mice die between embryonic days E8.5 and E10 due to impaired production of mature erythroid cells from progenitor cells. In Rnh1-deficient embryos, mRNA levels of Gata1 are normal, but GATA1 protein levels are decreased. At the molecular level, we found that RNH1 binds to the 40S subunit of ribosomes and facilitates polysome formation on Gata1 mRNA to confer transcript-specific translation. Further, RNH1 knockdown in human [CD34.sup.+] progenitor cells decreased erythroid differentiation without affecting myelopoiesis. Our results reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis., Introduction Regulation of gene expression is important for normal development. Recent studies show that ribosomal proteins (RPs) regulate gene expression by selectively facilitating translation of specific mRNAs (1, 2). For [...]

Published
2018
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30. Down syndrome and leukemia: from basic mechanisms to clinical advances

Author

Baruchel, Andre; https://orcid.org/0000-0003-0120-6089, Bourquin, Jean-Pierre; https://orcid.org/0000-0001-6571-6227, Crispino, John; https://orcid.org/0000-0002-8182-8306, Cuartero, Sergi, Hasle, Henrik; https://orcid.org/0000-0003-3976-9231, Hitzler, Johann, Klusmann, Jan-Henning; https://orcid.org/0000-0002-1070-0727, Izraeli, Shai; https://orcid.org/0000-0002-6938-2540, Lane, Andrew A, Malinge, Sebastien; https://orcid.org/0000-0002-9533-7778, Rabin, Karen R, Roberts, Irene, Ryeom, Sandra, Tasian, Sarah K, Wagenblast, Elvin, Baruchel, Andre; https://orcid.org/0000-0003-0120-6089, Bourquin, Jean-Pierre; https://orcid.org/0000-0001-6571-6227, Crispino, John; https://orcid.org/0000-0002-8182-8306, Cuartero, Sergi, Hasle, Henrik; https://orcid.org/0000-0003-3976-9231, Hitzler, Johann, Klusmann, Jan-Henning; https://orcid.org/0000-0002-1070-0727, Izraeli, Shai; https://orcid.org/0000-0002-6938-2540, Lane, Andrew A, Malinge, Sebastien; https://orcid.org/0000-0002-9533-7778, Rabin, Karen R, Roberts, Irene, Ryeom, Sandra, Tasian, Sarah K, and Wagenblast, Elvin

Abstract

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field.

Published
2023

33. 3159 – A SINGLE-CELL PROTEIN-TRANSCRIPTOME ATLAS OF HAEMATOPOIESIS ACROSS THE HUMAN LIFESPAN

Author

Londoño, Mariana Quiroga, primary, Mende, Nicole, additional, Stephenson, Emily, additional, Iskander, Deena, additional, Isobe, Tomoya, additional, Webb, Simone, additional, Goh, Issac, additional, Shanmugiah, Vijaya Mahalingam, additional, Hannah, Rebecca, additional, Roy, Anindita, additional, Roberts, Irene, additional, Laurenti, Elisa, additional, Haniffa, Muzlifah, additional, Wilson, Nicola K, additional, and Göttgens, Berthold, additional

Published
2023
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36. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762

Author

Chaidos, Aristeidis, Caputo, Valentina, Gouvedenou, Katerina, Liu, Binbin, Marigo, Ilaria, Chaudhry, Mohammed Suhail, Rotolo, Antonia, Tough, David F., Smithers, Nicholas N., Bassil, Anna K., Chapman, Trevor D., Harker, Nicola R., Barbash, Olena, Tummino, Peter, Al-Mahdi, Niam, Haynes, Andrea C., Cutler, Leanne, Le, BaoChau, Rahemtulla, Amin, Roberts, Irene, Kleijnen, Maurits, Witherington, Jason J., Parr, Nigel J., Prinjha, Rab K., and Karadimitris, Anastasios

Published
2014
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37. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Author

Dixon, Peter H., Levine, Adam P., Cebola, Inês, Chan, Melanie M. Y., Amin, Aliya S., Aich, Anshul, Mozere, Monika, Maude, Hannah, Mitchell, Alice L., Zhang, Jun, Adlard, Julian, Ahmed, Munaza, Aitman, Tim, Alachkar, Hana, Allsup, David, Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Astle, William, Attwood, Anthony, Babbs, Chris, Bakchoul, Tamam, Bariana, Tadbir, Barwell, Julian, Bennett, David, Bentley, David, Bierzynska, Agnieszka, Biss, Tina, Bleda, Marta, Bogaard, Harm, Bourne, Christian, Boyce, Sara, Bradley, John, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Michael, Buchan, Rachel, Buckland, Matthew, Bueser, Teofila, Burns, Siobhan, Burren, Oliver, Calleja, Paul, Carr-White, Gerald, Carss, Keren, Casey, Ruth, Caulfield, Mark, Chambers, John, Chambers, Jennifer, Cheng, Floria, Chinnery, Patrick F., Christian, Martin, Church, Colin, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor, Collins, Janine, Collins, Peter, Colombo, Camilla, Condliffe, Robin, Cook, Stuart, Cook, Terry, Cooper, Nichola, Corris, Paul, Crisp-Hihn, Abigail, Curry, Nicola, Danesino, Cesare, Daniels, Matthew, Daugherty, Louise, Davis, John, Deevi, Sri V. V., Dent, Timothy, Dewhurst, Eleanor, Dixon, Peter, Downes, Kate, Drazyk, Anna, Drewe, Elizabeth, Dutt, Tina, Edgar, David, Edwards, Karen, Egner, William, Erber, Wendy, Erwood, Marie, Estiu, Maria C., Evans, Gillian, Evans, Dafydd Gareth, Everington, Tamara, Eyries, Mélanie, Favier, Remi, Fletcher, Debra, Fox, James, Frary, Amy, French, Courtney, Freson, Kathleen, Frontini, Mattia, Gale, Daniel, Gall, Henning, Geoghegan, Claire, Gerighty, Terry, Ghio, Stefano, Ghofrani, Hossein-Ardeschir, Gibbs, Simon, Gilmour, Kimberley, Girerd, Barbara, Goddard, Sarah, Gomez, Keith, Gordins, Pavels, Gosal, David, Gräf, Stefan, Grassi, Luigi, Greene, Daniel, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell, Grozeva, Detelina, Hackett, Scott, Hadinnapola, Charaka, Hague, William, Haimel, Matthias, Hall, Matthew, Hanson, Helen, Harkness, Kirsty, Harper, Andrew, Harris, Claire, Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Hoffmann, Jonathan, Horvath, Rita, Houweling, Arjan, Howard, Luke, Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud, Humbert, Marc, Humphray, Sean, Hunter, Sarah, Hurles, Matthew, Izatt, Louise, James, Roger, Johnson, Sally, Jolles, Stephen, Jolley, Jennifer, Jurkute, Neringa, Kasanicki, Mary, Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kiely, David, Kingston, Nathalie, Klima, Robert, Kostadima, Myrto, Kovacs, Gabor, Koziell, Ania, Kreuzhuber, Roman, Kuijpers, Taco, Kumar, Ajith, Kumararatne, Dinakantha, Kuria, Manju, Laffa, Michael, Lalloo, Fiona, Lamber, Michele, Alle, Hana Lango, Lawrie, Allan, Layton, Mark, Lentaigne, Claire, Levine, Adam, Linger, Rachel, Longhurst, Hilary, Louka, Eleni, Ross, Robert MacKenzie, Madan, Bella, Maher, Eamonn, Maimaris, Jesmeen, Mangles, Sarah, Mapeta, Rutendo, Marchbank, Kevin, Marks, Stephen, Markus, Hugh S., Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark, Meacham, Stuart, Mead, Adam, Megy, Karyn, Mehta, Sarju, Michaelides, Michel, Millar, Carolyn, Moledina, Shahin, Montani, David, Moor, Tony, Morrell, Nicholas, Muir, Keith, Mumford, Andrew, Newnham, Michael, O'Sullivan, Jennifer, Obaji, Samya, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Ormondroy, Elizabeth, Ouwehan, Willem, Papadi, Sofia, Park, Soo-Mi, Parry, David, Paterson, Joan, Peacock, Andrew, Peden, John, Peerlinck, Kathelijne, Penkett, Christopher, Pepke-Zaba, Joanna, Petersen, Romina, Pyle, Angela, Rankin, Stuart, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthew, Paula, Rees, Christine, Rendon, Augusto, Renton, Tara, Rice, Andrew, Richardson, Sylvia, Richter, Alex, Roberts, Irene, Roughley, Catherine, Roy, Noemi, Sadeghi-Alavijeh, Omid, Saleem, Moin, Samani, Nilesh, Sanchis-Juan, Alba, Sargur, Ravishankar, Satchell, Simon, Savic, Sinisa, Scelsi, Laura, Schulman, Sol, Scully, Marie, Searle, Claire, Seeger, Werner, Sewell, Carrock, Seyres, Denis, Shapiro, Susie, Sharmardina, Olga, Shtoyerman, Rakefet, Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael, Sivapalaratnam, Suthesh, Skytte, Anne-Bine, Smith, Katherine, Smith, Kenneth G. C., Snape, Katie, Soubrier, Florent, Staines, Simon, Staples, Emily, Stark, Hannah, Stephens, Jonathan, Stirrups, Kathleen, Stock, Sophie, Suntharalingam, Jay, Swietlik, Emilia, Tait, R. Campbell, Talks, Kate, Tan, Rhea, Thaventhiran, James, Themistocleous, Andreas, Thomas, Moira, Thomson, Kate, Thrasher, Adrian, Thys, Chantal, Tischkowitz, Marc, Titterton, Catherine, Toh, Cheng-Hock, Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Trembath, Richard, Tuna, Salih, Turek, Wojciech, Turro, Ernest, Vale, Tom, Van Geet, Chris, Van Zuydam, Natalie, Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Noordegraaf, Anton Vonk, Waisfisz, Quintin, Walker, Suellen, Ware, James, Watkins, Hugh, Watt, Christopher, Webster, Andrew, Wei, Wei, Welch, Steven, Wessels, Julie, Westbury, Sarah, Westwood, John-Paul, Wharton, John, Whitehorn, Deborah, Whitworth, James, Wilkins, Martin R., Wong, Edwin, Wood, Nicholas, Wood, Yvette, Woods, Geoff, Woodward, Emma, Wort, Stephen, Worth, Austen, Yates, Katherine, Yong, Patrick, Young, Tim, Yu, Ping, Yu-Wai-Man, Patrick, Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Fowler, T., Giess, A., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O'Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Chambers, Jenny, Syngelaki, Argyro, Donnelly, Jennifer, Cooley, Sharon, Geary, Michael, Nicolaides, Kypros, Thorsell, Malin, Hague, William M., Estiu, Maria Cecilia, Marschall, Hanns-Ulrich, Gale, Daniel P., Williamson, Catherine, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Pediatrics, Foundation for the National Institutes of Health (FNIH), The Academy of Medical Sciences, British Heart Foundation, Imperial College Healthcare NHS Trust- BRC Funding, Paediatric Infectious Diseases / Rheumatology / Immunology, and ARD - Amsterdam Reproduction and Development

Subjects
VARIANT, LOCI, INTEGRATIVE ANALYSIS, General Physics and Astronomy, Cholestasis, Intrahepatic, TRIGLYCERIDE LEVELS, DISEASE, General Biochemistry, Genetics and Molecular Biology, Bile Acids and Salts, Pregnancy, Humans, MUTATION, Science & Technology, Multidisciplinary, Genomics England Research Consortium Collaborators, Infant, Newborn, NIHR BioResource, General Chemistry, GLUCOCORTICOID-RECEPTOR, Multidisciplinary Sciences, ALKALINE SPHINGOMYELINASE, Pregnancy Complications, INSIGHTS, Science & Technology - Other Topics, Premature Birth, Female, FASTING GLUCOSE, Genome-Wide Association Study
Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

Published
2022
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41. Multi-organ functions of yolk sac during human early development

Author

Botting, Rachel A, primary, Goh, Issac, additional, Rose, Antony, additional, Webb, Simone, additional, Engelbert, Justin, additional, Gitton, Yorick, additional, Stephenson, Emily, additional, Quiroga Londoño, Mariana, additional, Mather, Michael, additional, Mende, Nicole, additional, Imaz-Rosshandler, Ivan, additional, Horsfall, Dave, additional, Basurto-Lozada, Daniela, additional, Chipampe, Nana-Jane, additional, Rook, Victoria, additional, Mazin, Pavel, additional, Vijayabaskar, MS, additional, Hannah, Rebecca, additional, Gambardella, Laure, additional, Green, Kile, additional, Ballereau, Stephane, additional, Inoue, Megumi, additional, Tuck, Liz, additional, Lorenzi, Valentina, additional, Kwakwa, Kwasi, additional, Alsinet, Clara, additional, Olabi, Bayanne, additional, Miah, Mohi, additional, Admane, Chloe, additional, Popescu, Dorin-Mirel, additional, Acres, Meghan, additional, Dixon, David, additional, Coulthard, Rowen, additional, Lisgo, Steven, additional, Henderson, Deborah J, additional, Dann, Emma, additional, Suo, Chenqu, additional, Kinston, Sarah J, additional, Park, Jong-eun, additional, Polanski, Krzysztof, additional, Van Dongen, Stijn, additional, Meyer, Kerstin B, additional, de Bruijn, Marella, additional, Palis, James, additional, Behjati, Sam, additional, Laurenti, Elisa, additional, Wilson, Nicola K, additional, Vento-Tormo, Roser, additional, Chédotal, Alain, additional, Bayraktar, Omer, additional, Roberts, Irene, additional, Jardine, Laura, additional, Göttgens, Berthold, additional, Teichmann, Sarah A, additional, and Haniffa, Muzlifah, additional

Published
2022
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42. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia

Author

Roberts, Irene, Alford, Kate, Hall, Georgina, Juban, Gaetan, Richmond, Helen, Norton, Alice, Vallance, Grant, Perkins, Kelly, Marchi, Emanuele, McGowan, Simon, Roy, Anindita, Cowan, Gillian, Anthony, Mark, Gupta, Amit, Ho, John, Uthaya, Sabita, Curley, Anna, Rasiah, Shree Vishna, Watts, Timothy, Nicholl, Richard, Bedford-Russell, Alison, Blumberg, Raoul, Thomas, Angela, Gibson, Brenda, Halsey, Chris, Lee, Pek-Wan, Godambe, Sunit, Sweeney, Connor, Bhatnagar, Neha, Goriely, Anne, Campbell, Peter, and Vyas, Paresh

Published
2013
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44. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling

Author

Locatelli, Franco, Kabbara, Nabil, Ruggeri, Annalisa, Ghavamzadeh, Ardeshir, Roberts, Irene, Li, Chi Kong, Bernaudin, Françoise, Vermylen, Christiane, Dalle, Jean-Hugues, Stein, Jerry, Wynn, Robert, Cordonnier, Catherine, Pinto, Fernando, Angelucci, Emanuele, Socié, Gérard, Gluckman, Eliane, Walters, Mark C., and Rocha, Vanderson

Published
2013
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46. Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma

Author

Chaidos, Aristeidis, Barnes, Chris P., Cowan, Gillian, May, Philippa C., Melo, Valeria, Hatjiharissi, Evdoxia, Papaioannou, Maria, Harrington, Heather, Doolittle, Helen, Terpos, Evangelos, Dimopoulos, Meletios, Abdalla, Saad, Yarranton, Helen, Naresh, Kikkeri, Foroni, Letizia, Reid, Alistair, Rahemtulla, Amin, Stumpf, Michael, Roberts, Irene, and Karadimitris, Anastasios

Published
2013
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48. CD34+CD19−CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies

Author

European Research Council, European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Cancer Research UK, Wellcome Trust, Generalitat de Catalunya, University of Oxford, Bueno, Clara, Barrera, Susana, Bataller, Alex, Ortiz-Maldonado, Valentín, Elliot, Natalina, O’Byrne, Sorcha, Wang, Guanlin, Rovira, Montserrat, Gutierrez-Aguera, Francisco, Trincado, Juan L., González-González, María, Morgades, Mireia, Sorigué, Marc, Bárcena, Paloma, Zanetti, Samanta Romina, Torrebadell, Montse, Vega-García, Nerea, Rives, Susana, Mallo, Mar, Solé, Francesc, Mead, Adam J., Roberts, Irene, Thongjuea, Supat, Psaila, Bethan, Juan, Manel, Delgado, Julio, Urbano-Ispizúa, Álvaro, Ribera, Josep-Maria, Orfao, Alberto, Roy, Anindita, Menéndez, Pablo, European Research Council, European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Cancer Research UK, Wellcome Trust, Generalitat de Catalunya, University of Oxford, Bueno, Clara, Barrera, Susana, Bataller, Alex, Ortiz-Maldonado, Valentín, Elliot, Natalina, O’Byrne, Sorcha, Wang, Guanlin, Rovira, Montserrat, Gutierrez-Aguera, Francisco, Trincado, Juan L., González-González, María, Morgades, Mireia, Sorigué, Marc, Bárcena, Paloma, Zanetti, Samanta Romina, Torrebadell, Montse, Vega-García, Nerea, Rives, Susana, Mallo, Mar, Solé, Francesc, Mead, Adam J., Roberts, Irene, Thongjuea, Supat, Psaila, Bethan, Juan, Manel, Delgado, Julio, Urbano-Ispizúa, Álvaro, Ribera, Josep-Maria, Orfao, Alberto, Roy, Anindita, and Menéndez, Pablo

Abstract

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.

Published
2022

49. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Author

Hadinnapola, Charaka, Bleda, Marta, Haimel, Matthias, Screaton, Nicholas, Swift, Andrew, Dorfmüller, Peter, Preston, Stephen D., Southwood, Mark, Hernandez-Sanchez, Jules, Martin, Jennifer, Treacy, Carmen, Yates, Katherine, Bogaard, Harm, Church, Colin, Coghlan, Gerry, Condliffe, Robin, Corris, Paul A., Gibbs, Simon, Girerd, Barbara, Holden, Simon, Humbert, Marc, Kiely, David G., Lawrie, Allan, Machado, Rajiv, MacKenzie Ross, Robert, Moledina, Shahin, Montani, David, Newnham, Michael, Peacock, Andrew, Pepke-Zaba, Joanna, Rayner-Matthews, Paula, Shamardina, Olga, Soubrier, Florent, Southgate, Laura, Suntharalingam, Jay, Toshner, Mark, Trembath, Richard, Noordegraaf, Anton Vonk, Wilkins, Martin R., Wort, Stephen J., Wharton, John, Gräf, Stefan, Morrell, Nicholas W., Aitman, Timothy, Bennett, David, Caulfield, Mark, Chinnery, Patrick, Gale, Daniel, Koziell, Ania, Kuijpers, Taco W, Laffan, Michael A, Maher, Eamonn, Markus, Hugh S, Ouwehand, Willem H, Perry, David, Raymond, F Lucy, Roberts, Irene, Smith, Kenneth, Thrasher, Adrian, Watkins, Hugh, Williamson, Catherine, Woods, Geoffrey, Ashford, Sofie, Bradley, John R, Fletcher, Debra, Hammerton, Tracey, James, Roger, Kingston, Nathalie, Ouwehand, Willem H, Penkett, Christopher J, Raymond, F Lucy, Stirrups, Kathleen, Veltman, Marijke, Young, Tim, Ashford, Sofie, Brown, Matthew, Clements-Brod, Naomi, Davis, John, Dewhurst, Eleanor, Erwood, Marie, Frary, Amy, Linger, Rachel, Papadia, Sofia, Rehnstrom, Karola, Stark, Hannah, Allsup, David, Austin, Steve, Bakchoul, Tamam, Bariana, Tadbir K, Bolton-Maggs, Paula, Chalmers, Elizabeth, Collins, Peter, Erber, Wendy N, Everington, Tamara, Favier, Remi, Freson, Kathleen, Furie, Bruce, Gattens, Michael, Gomez, Keith, Greene, Daniel, Greinacher, Andreas, Hart, Daniel, Heemskerk, Johan WM, Henskens, Yvonne, Kazmi, Rashid, Keeling, David, Kelly, Anne M, Laffan, Michael A, Lambert, Michele P, Lentaigne, Claire, Liesner, Ri, Mangles, Sarah, Mathias, Mary, Millar, Carolyn M, Mumford, Andrew, Nurden, Paquita, Ouwehand, Willem H, Papadia, Sofia, Payne, Jeanette, Pasi, John, Perry, David J, Peerlinck, Kathelijne, Richards, Michael, Rondina, Matthew, Roughley, Catherine, Schulman, Sol, Schulze, Harald, Scully, Marie, Sivapalaratnam, Suthesh, Tait, R Campbell, Talks, Kate, Thachil, Jecko, Turro, Ernest, Toh, Cheng-Hock, Van Geet, Chris, De Vries, Minka, Warner, Timothy Q, Westbury, Sarah, Furnell, Abigail, Mapeta, Rutendo, Simeoni, Ilenia, Staines, Simon, Stephens, Jonathan, Stirrups, Kathleen, Whitehorn, Deborah, Watt, Christopher, Attwood, Antony, Daugherty, Louise, Deevi, Sri VV, Halmagyi, Csaba, Hu, Fengyuan, James, Roger, Matser, Vera, Meacham, Stuart, Megy, Karyn, Penkett, Christopher J, Stirrups, Kathleen, Titterton, Catherine, Tuna, Salih, Yu, Ping, von Ziegenweldt, Julie, Astle, William, Carss, Keren, Greene, Daniel, Lango-Allen, Hana, Turro, Ernest, Astle, William, Greene, Daniel, Richardson, Sylvia, Turro, Ernest, Calleja, Paul, Rankin, Stuart, Turek, Wojciech, Bryson, Christine, Anderson, Julie, Fletcher, Debra, McJannet, Coleen, Stock, Sophie, Young, Tim, Wassmer, Evangeline, Sohal, Aman, Santra, Saikat, Vogt, Julie, Chitre, Manali, Krishnakumar, Deepa, Ambegaonkar, Gautum, Maw, Anna, Armstrong, Ruth, Park, Soo-Mi, Mehta, Sarju, Paterson, Joan, Carmichael, Jenny, Allen, Louise, Hensiek, Anke, Firth, Helen, Stein, Penelope, Deegan, Patrick, Doffinger, Rainer, Parker, Alasdair, Bitner-Glindzicz, Maria, Scott, Richard, Hurst, Jane, Rosser, Elisabeth, Lees, Melissa, Clement, Emma, Henderson, Robert, Thompson, Dorothy, Gardham, Alice, Gissen, Paul, Josifova, Dragana, Thomas, Ellen, Patch, Chris, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Canham, Natalie, Wakeling, Emma, Holder, Susan, Ghali, Neeti, Brady, Angie, Clowes, Virginia, MacLaren, Robert, Webster, Andrew, Moore, Anthony, Arno, Gavin, Michaelides, Michel, Rankin, Julia, Kurian, Manju, Murphy, Elaine, Carss, Keren, Sanchis-Juan, Alba, Erwood, Marie, Dewhurst, Eleanor, Grozeva, Detelina, Raymond, F Lucy, Reid, Evan, Woods, Geoff, Tischkowitz, Marc, Sandford, Richard, Ali, Sonia, Creaser-Myers, Amanda, Cookson, Victoria, DaCosta, Rosa, Dormand, Natalie, Ghataorhe, Pavandeep K, Greenhalgh, Alan, Huis in’t Veld, Anna, Kennedy, Fiona, Mackenzie Ross, Rob, Masati, Larahmie, Meehan, Sharon, Othman, Shokri, Pollock, Val, Polwarth, Gary, Rhodes, Christopher J, Rue-Albrecht, Kevin, Schotte, Gwen, Shipley, Debbie, Tan, Yvonne, Wanjiku, Ivy, Wort, John, Smith, Kenneth, Kuijpers, Taco, Thrasher, Adrian, Thaventhiran, James, Brown, Matthew, Lango Allen, Hana, Simeoni, Ilenia, Staples, Emily, Samarghitean, Crina, Alachkar, Hana, Antrobus, Richard, Arumugakani, Gururaj, Bacchelli, Chiara, Baxendale, Helen, Bethune, Claire, Bibi, Shahnaz, Booth, Claire, Browning, Michael, Burns, Siobhan, Chandra, Anita, Cooper, Nichola, Davies, Sophie, Devlin, Lisa, Doffinger, Rainer, Drewe, Elizabeth, Edgar, David, Egner, William, Ghurye, Rohit, Gilmour, Kimberley, Goddard, Sarah, Gordins, Pavel, Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Hayman, Grant, Herwadkar, Archana, Huissoon, Aarnoud, Jolles, Stephen, Kelleher, Peter, Kumararatne, Dinakantha, Lear, Sara, Longhurst, Hilary, Lorenzo, Lorena, Maimaris, Jesmeen, Manson, Ania, McDermott, Elizabeth, Murng, Sai, Nejentsev, Sergey, Noorani, Sadia, Oksenhendler, Eric, Ponsford, Mark, Qasim, Waseem, Quinti, Isabella, Richter, Alex, Sargur, Ravishankar, Savic, Sinisa, Seneviratne, Suranjith, Sewell, Carrock, Stauss, Hans, Thomas, Moira, Welch, Steve, Willcocks, Lisa, Yeatman, Nigel, and Yong, Patrick

Published
2017
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50. Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

Author

Ersek, Adel, Xu, Ke, Antonopoulos, Aristotelis, Butters, Terry D., Santo, Ana Espirito, Vattakuzhi, Youridies, Williams, Lynn M., Goudevenou, Katerina, Danks, Lynett, Freidin, Andrew, Spanoudakis, Emmanouil, Parry, Simon, Papaioannou, Maria, Hatjiharissi, Evdoxia, Chaidos, Aristeidis, Alonzi, Dominic S., Twigg, Gabriele, Hu, Ming, Dwek, Raymond A., Haslam, Stuart M., Roberts, Irene, Dell, Anne, Rahemtulla, Amin, Horwood, Nicole J., and Karadimitris, Anastasios

Subjects
Research, Health care industry
Abstract

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NBDNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM., Introduction Sphingolipids and their glycosylated derivatives, glycosphingolipids (GSLs), are essential structural components of mammalian cell membranes and are characterized by heterogenic composition among tissues and even in the same cell [...]

Published
2015
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