6 results on '"Barcella M"'
Number of results to display per page
Search Results
2. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index
- Author
-
Hoggart, C, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, J, Teumer, A, Winkler, T, Tšernikova, N, Luan, J, Mihailov, E, Ehret, G, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, P, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, D, Hayward, C, Lopez, M, Franke, L, Russo, A, Heid, I, Salvi, E, Vendantam, S, Arking, D, Boerwinkle, E, Chambers, J, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, J, Porteous, D, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, BRAMBILLA, PAOLO, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hebebrand, J, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Moradpour, D, Iranzo, A, Kemp, J, Lammers, G, Aubert, V, Heim, M, Peraita Adrados, R, Santamaria, J, Negro, F, Schmidt, C, Scott, R, Strauch, K, Völzke, H, Yuan, W, Bell, J, Chakravarti, A, Kooner, J, Matullo, G, Whitfield, J, Paccaud, F, Bergmann, S, Beckmann, J, Tafti, M, Hastie, N, Bochud, M, Da Smith, G, Rousson, V, Rivolta, C, Kutalik, Z., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Hoggart, Clive J, Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Benyamin, Beben, Kutalik, Zoltan, Generation Scotland Consortium, GIANT Consortium, LifeLines Cohort study, Cardiology, Vascular Medicine, Plastic, Reconstructive and Hand Surgery, Amsterdam Cardiovascular Sciences, Medical Research Council (MRC), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Haartman Institute (-2014), Transplantation Laboratory, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hoggart, Cj, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, Jh, Teumer, A, Winkler, Tw, Tšernikova, N, Luan, J, Mihailov, E, Ehret, Gb, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, Py, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, Dm, Hayward, C, Lopez, Mf, Franke, L, Russo, A, Heid, Im, Salvi, E, Vendantam, S, Arking, De, Boerwinkle, E, Chambers, Jc, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, Je, Porteous, D, GENERATION SCOTLAND, Consortium, LIFELINES COHORT, Study, Giant, Consortium, Manunta, Paolo, Moradpour, D, Iranzo, A, Hebebrand, J, Kemp, Jp, Lammers, Gj, Aubert, V, Heim, Mh, Martin, Ng, Montgomery, Gw, PERAITA ADRADOS, R, Santamaria, J, Negro, F, Schmidt, Co, Scott, Ra, Spector, Td, Strauch, K, Völzke, H, Wareham, Nj, Yuan, W, Bell, Jt, Chakravarti, A, Kooner, J, Peters, A, Matullo, G, Wallaschofski, H, Whitfield, Jb, Paccaud, F, Vollenweider, P, Bergmann, S, Beckmann, J, Tafti, M, Hastie, Nd, Cusi, D, Bochud, M, Frayling, Tm, Metspalu, A, Jarvelin, Mr, Scherag, A, Smith, Gd, Borecki, Ib, Rousson, V, Hirschhorn, Jn, Rivolta, C, Loos, Rj, Kutalik, Z., Hoggart, C, Zhao, J, Winkler, T, Ehret, G, Bochud, P, Evans, D, Lopez, M, Heid, I, Arking, D, Chambers, J, Huffman, J, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Kemp, J, Lammers, G, Heim, M, Peraita Adrados, R, Schmidt, C, Scott, R, Bell, J, Whitfield, J, Hastie, N, and Da Smith, G
- Subjects
Epigenomics ,Male ,Netherlands Twin Register (NTR) ,body mass index ,gene ,SNP ,Cancer Research ,BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Potassium Channels ,Glucose Transport Proteins, Facilitative ,Medizin ,Genome-wide association study ,CHILDREN ,ddc:616.07 ,FAMILIES ,Body Mass Index ,0302 clinical medicine ,Polymorphism (computer science) ,Genotype ,LifeLines Cohort study ,GENETICS & HEREDITY ,Tandem Pore Domain ,Genetics (clinical) ,ASSOCIATIONS ,ddc:616 ,Genetics ,0303 health sciences ,QUANTITATIVE TRAIT LOCI ,Ecology ,Genomics ,Single Nucleotide ,Generation Scotland Consortium ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,OBESITY ,Physical Sciences ,KCNK9 protein ,Epigenetics ,Female ,ALCOHOLISM ,Glucose Transport Proteins ,Life Sciences & Biomedicine ,Statistics (Mathematics) ,Human ,Research Article ,VARIANCES ,Adult ,PENETRANCE ,GENES ,lcsh:QH426-470 ,Evolution ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Biostatistics ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Genomic Imprinting ,Potassium Channels, Tandem Pore Domain ,Genetic ,Behavior and Systematics ,SDG 3 - Good Health and Well-being ,Genetic linkage ,GIANT Consortium ,Genome-Wide Association Studies ,Humans ,Genetic Predisposition to Disease ,Statistical Methods ,Allele ,Polymorphism ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Gene Expression Regulation ,Genome-Wide Association Study ,Obesity ,030304 developmental biology ,0604 Genetics ,Science & Technology ,LINKAGE ANALYSIS ,SLC2A10 protein ,Biology and Life Sciences ,Computational Biology ,Facilitative ,Genome Analysis ,Ecology, Evolution, Behavior and Systematic ,lcsh:Genetics ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,3111 Biomedicine ,Genomic imprinting ,Mathematics ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P, Author Summary Large genetic association studies have revealed many genetic factors influencing common traits, such as body mass index (BMI). These studies assume that the effect of genetic variants is the same regardless of whether they are inherited from the mother or the father. In our study, we have developed a new approach that allows us to investigate variants whose impact depends on their parental origin (parent-of-origin effects), in unrelated samples when the parental origin cannot be inferred. This is feasible because at genetic markers at which such effects occur there is increased variability of the trait among individuals who inherited different genetic codes from their mother and their father compared to individuals who inherited the same genetic code from both parents. We applied this methodology to discover genetic markers with parent-of-origin effects (POEs) on BMI. This resulted in six candidate markers showing strong POE association. We then attempted to replicate the POE effects of these markers in family studies (where one can infer the parental origin of the inherited variants). Two of our candidates showed significant association in the family studies, the paternal and maternal effects of these markers were in the opposite direction.
- Published
- 2014
- Full Text
- View/download PDF
3. CIITA-DEPENDENT TRANSCRIPTIONAL DOWNREGULATION OF HLA CLASS II RESULTS IN LEUKEMIA IMMUNE ESCAPE AND RELAPSE AFTER ALLOGENEIC HSCT
- Author
-
Toffalori, C., Riba, M., Zito, L., Barcella, M., Spinelli, O., Crucitti, L., Peccatori, J., Bernardi, M., Bonini, C., Cittaro, D., Lazarevic, D., Rambaldi, A., Barlassina, C., Stupka, E., Ciceri, F., Fleischhauer, Katharina, Vago, L., Toffalori, C, Riba, M, Zito, L, Barcella, M, Spinelli, O, Crucitti, L, Peccatori, J, Bernardi, M, Bonini, C, Cittaro, D, Lazarevic, D, Rambaldi, A, Barlassina, C, Stupka, E, Ciceri, F, Fleischhauer, K, and Vago, L
- Subjects
Medizin ,ComputingMethodologies_GENERAL - Abstract
Poster Abstract
- Published
- 2014
4. Leukemia relapse after allogenic HSCT displays a distinctive immune-related signature, with functionally relevant alterations in HLA Class II antigen presentation and T-Cell costimulation
- Author
-
Toffalori, C., Riba, M., Zito, L., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Crucitti, L., Cieri, N., Cittaro, D., Lazarevic, D., Peccatori, J., Bernardi, M., Bonini, C., Rambaldi, A., Barlassina, C., Stupka, E., Bianchi, M., Ciceri, F., Fleischhauer, Katharina, and Vago, L.
- Subjects
Medizin - Published
- 2015
5. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
- Author
-
Leo Luznik, Luca Vago, Dietrich W. Beelen, Elisa Montaldo, Matteo Barcella, Robert Zeiser, Bernhard Gentner, Gabriele Bucci, Raynier Devillier, Renato Ostuni, Matteo Carrabba, Masahiro Onozawa, Valentina Gambacorta, Orietta Spinelli, Miguel Waterhouse, Katharina Fleischhauer, Elia Stupka, Ivana Gojo, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Raffaella Greco, Michela Riba, Matteo Maria Naldini, Dejan Lazarevic, Massimo Bernardi, Maddalena Noviello, Davide Cittaro, Takanori Teshima, Didier Blaise, Jacopo Peccatori, Cristina Barlassina, Francesco Manfredi, Giovanni Tonon, Giacomo Oliveira, Alessandro Rambaldi, Constantijn J.M. Halkes, Marieke Griffioen, Maher Hanoun, Nicoletta Cieri, Fabio Ciceri, Jürgen Finke, Toffalori, C., Zito, L., Gambacorta, V., Riba, M., Oliveira, G., Bucci, G., Barcella, M., Spinelli, O., Greco, R., Crucitti, L., Cieri, N., Noviello, M., Manfredi, F., Montaldo, E., Ostuni, R., Naldini, M. M., Gentner, B., Waterhouse, M., Zeiser, R., Finke, J., Hanoun, M., Beelen, D. W., Gojo, I., Luznik, L., Onozawa, M., Teshima, T., Devillier, R., Blaise, D., Halkes, C. J. M., Griffioen, M., Carrabba, M. G., Bernardi, M., Peccatori, J., Barlassina, C., Stupka, E., Lazarevic, D., Tonon, G., Rambaldi, A., Cittaro, D., Bonini, C., Fleischhauer, K., Ciceri, F., Vago, L., Toffalori, C, Zito, L, Gambacorta, V, Riba, M, Oliveira, G, Bucci, G, Barcella, M, Spinelli, O, Greco, R, Crucitti, L, Cieri, N, Noviello, M, Manfredi, F, Montaldo, E, Ostuni, R, Naldini, M, Gentner, B, Waterhouse, M, Zeiser, R, Finke, J, Hanoun, M, Beelen, D, Gojo, I, Luznik, L, Onozawa, M, Teshima, T, Devillier, R, Blaise, D, Halkes, C, Griffioen, M, Carrabba, M, Bernardi, M, Peccatori, J, Barlassina, C, Stupka, E, Lazarevic, D, Tonon, G, Rambaldi, A, Cittaro, D, Bonini, C, Fleischhauer, K, Ciceri, F, and Vago, L
- Subjects
0301 basic medicine ,Myeloid ,medicine.medical_treatment ,Antigen presentation ,Medizin ,Reproducibility of Result ,Hematopoietic stem cell transplantation ,Lymphocyte Activation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,RNA, Messenger ,Transplantation, Homologou ,business.industry ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Histocompatibility Antigens Class II ,Hematopoietic Stem Cell Transplantation ,Reproducibility of Results ,Myeloid leukemia ,General Medicine ,medicine.disease ,Transplantation ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,business ,CD80 ,Human - Abstract
Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-gamma or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
- Published
- 2019
6. Acute Myeloid Leukemia Relapses after Allogenenic HSCT Display a Distinctive Immune-Related Signature, with Frequent and Functionally Relevant Alterations in HLA Class II Antigen Presentation and T Cell Costimulation
- Author
-
Elia Stupka, Katharina Fleischhauer, Nicoletta Cieri, Chiara Bonini, Cristina Toffalori, Lara Crucitti, Laura Zito, Davide Cittaro, Luca Vago, Matteo Barcella, Dejan Lazarevic, Michela Riba, Cristina Barlassina, Alessandro Rambaldi, Massimo Bernardi, Fabio Ciceri, Jacopo Peccatori, Orietta Spinelli, Toffalori, C, Riba, M, Zito, L, Barcella, M, Spinelli, O, Crucitti, L, Cieri, N, Peccatori, J, Bernardi, M, Bonini, C, Cittaro, D, Lazarevic, D, Rambaldi, A, Barlassina, C, Stupka, E, Ciceri, F, Fleischhauer, K, and Vago, L
- Subjects
medicine.medical_treatment ,T cell ,Immunology ,Antigen presentation ,Medizin ,Myeloid leukemia ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Biology ,medicine.disease ,Biochemistry ,Histocompatibility ,Leukemia ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Lymphocyte costimulation ,medicine - Abstract
INTRODUCTION: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) represents an effective form of adoptive immunotherapy for Acute Myeloid Leukemia (AML), thanks to the antitumor effect mediated by donor immune cells infused as part of the graft. Unfortunately, post-transplantation relapses remain a frequent observation, warranting further investigation on AML immunobiology. Our group demonstrated that relapses after partially HLA-incompatible HSCT are frequently due to the outgrowth of immune-resistant mutant AML clones characterized by genomic loss the mismatched histocompatibility determinants targeted by alloreactive donor T cells, and have thus gained a selective advantage upon pressure from the transplanted immune system, in a process called “leukemia immunoediting” (Vago et al., N Engl J Med, 2009). In the present study, we took advantage of high-throughput technologies to profile post-transplantation AML relapses with no genomic loss of HLA, to identify novel targets of the leukemia immunoediting process. METHODS: Serial AML samples were collected and FACS-purified from 9 patients at diagnosis, relapse after sole chemotherapy and relapse after allo-HSCT, and employed for whole transcriptome profiling using Illumina HumanHT12 microarrays. Deregulated genes were identified by pair-wise LIMMA analysis, and unsupervised enrichment analysis was performed interrogating the Gene Ontology database. High-throughput results were confirmed in a validation cohort of 12 patients by ad hoc designed qPCR assays, immunophenotypic analyses and functional experiments. In particular, co-cultures were performed using as responders peripheral blood lymphocytes harvested from patients after allo-HSCT, and as stimulators and targets their respective AML blasts collected at diagnosis or at relapse: read-outs included antigen-specific T cell activation, cytotoxicity, and cytokine release. RESULTS: Amongst all the genes expressed by purified AML blasts, a 110-gene signature (p CONCLUSIONS: Our results demonstrate that the deregulation of immune-related processes, and in particular of molecules and pathways involved in T cell-mediated allo-recognition, are pervasive and distinctive features of AML relapses after allo-HSCT. Identification of patient-specific mechanisms of immune evasion might be translated into personalized therapeutic approaches, tailored to restore or circumvent inefficient antigen presentation and T cell costimulation. Disclosures Bonini: MolMed S.p.A.: Consultancy.
- Published
- 2014
Catalog
Books, media, physical & digital resources
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.