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148 results on '"Muckenthaler, M"'

4. S108: PEDIATRIC T- ALL RELAPSE: CONSTITUTIONAL CANCER PREDISPOSITION AND HYPERMUTATATOR PHENOTYPES

Author

Richter-Pechanska, P., primary, Kunz, J., additional, Rausch, T., additional, Erarslan-Uysal, B., additional, Bornhauser, B., additional, Frismantas, V., additional, Assenov, Y., additional, Zimmermann, M., additional, Happich, M., additional, von Knebel-Doeberitz, C., additional, von Neuhoff, N., additional, Koehler, R., additional, Stanulla, M., additional, Schrappe, M., additional, Cario, G., additional, Escherich, G., additional, Kischner-Schwabe, R., additional, Eckert, C., additional, Avigad, S., additional, Pfister, S., additional, Muckenthaler, M., additional, Bourquin, J.-P., additional, Korbel, J., additional, and Kulozik, A., additional

Published
2022
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5. S277: HYPOFERREMIA CAUSED BY FERROPORTIN DOWNREGULATION IS REGULATED BY NFКB THROUGH HDAC-DEPENDENT MECHANISMS

Author

Marques, O., primary, Horvat, N., additional, Lai, M. C., additional, Zechner, L., additional, Colucci, S., additional, Sparla, R., additional, Zimmermann, S., additional, Neufeldt, C. J., additional, Altamura, S., additional, Zaugg, J., additional, Mudder, K., additional, Knopf, J. D., additional, Lemberg, M. K., additional, Pasparakis, M., additional, Hentze, M. W., additional, and Muckenthaler, M. U., additional

Published
2022
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6. S274: A NOVEL SUBTYPE OF ANEMIA CAUSED BY MUTATIONS IN TFRC GENE

Author

Colucci, S., primary, Venturi, V., additional, Nicole, F., additional, Jové Solavera, D., additional, Zimon, M., additional, Richter-Pechanska, P., additional, Hernandez, G., additional, Unal, S., additional, Gumruk, F., additional, Diaz-Conradi, A., additional, Romero-Cortadellas, L., additional, Ferrer-Cortès, X., additional, Olivella, M., additional, Erlacher, M., additional, Niemeyer, C., additional, Wiesel, T., additional, Pepperkok, R., additional, Fleming, M. D., additional, Kulozik, A. E., additional, Sanchez, M., additional, and Muckenthaler, M. U., additional

Published
2022
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7. Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

Author

Theobald, V, additional, Xanthouli, P, additional, Benjamin, N, additional, Marra, A, additional, D'Agostino, A, additional, Egenlauf, B, additional, Shaukat, M, additional, Ding, C, additional, Cittadini, A, additional, Bossone, E, additional, Koegler, M, additional, Grünig, E, additional, Muckenthaler, M, additional, and Eichstaedt, C, additional

Published
2022
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9. Maternal iron status in early pregnancy and DNA methylation in offspring:an epigenome-wide meta-analysis

Author

Taeubert, M. J., de Prado-Bert, P., Geurtsen, M. L., Mancano, G., Vermeulen, M. J., Reiss, I. K.M., Caramaschi, D., Sunyer, J., Sharp, G. C., Julvez, J., Muckenthaler, M. U., Felix, J. F., Taeubert, M. J., de Prado-Bert, P., Geurtsen, M. L., Mancano, G., Vermeulen, M. J., Reiss, I. K.M., Caramaschi, D., Sunyer, J., Sharp, G. C., Julvez, J., Muckenthaler, M. U., and Felix, J. F.

Abstract

Background: Unbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother–newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation. Results: Maternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs. Conclusion: Maternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in

Published
2022

10. Additional file 1 of Maternal iron status in early pregnancy and DNA methylation in offspring: an epigenome-wide meta-analysis

Author

Taeubert, M. J., de Prado-Bert, P., Geurtsen, M. L., Mancano, G., Vermeulen, M. J., Reiss, I. K. M., Caramaschi, D., Sunyer, J., Sharp, G. C., Julvez, J., Muckenthaler, M. U., and Felix, J. F.

Subjects
ComputingMilieux_COMPUTERSANDEDUCATION, ComputingMilieux_COMPUTERSANDSOCIETY, health care economics and organizations
Abstract

Additional file 1. Supplemental tables, cohort-specific methods, funding and acknowledgements.

Published
2022
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20. Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

Author

Pasricha, S., Lim, P., Duarte, T., Casu, C., Oosterhuis, D., Mleczko-Sanecka, K., Suciu, M., Da Silva, A., Al-Hourani, K., Arezes, J., McHugh, K., Gooding, S., Frost, J., Wray, K., Santos, A., Porto, G., Repapi, E., Gray, N., Draper, S., Ashley, N., Soilleux, E., Olinga, P., Muckenthaler, M., Hughes, J., Rivella, S., Milne, T., Armitage, A., Drakesmith, H., Pasricha, Sant-Rayn [0000-0002-5502-0434], Duarte, Tiago L [0000-0002-4901-4580], Draper, Simon J [0000-0002-9415-1357], Hughes, Jim R [0000-0002-8955-7256], Milne, Thomas A [0000-0002-0413-4271], Apollo - University of Cambridge Repository, Pharmaceutical Technology and Biopharmacy, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Groningen Institute for Organ Transplantation (GIOT)

Subjects
Male, inorganic chemicals, congenital, hereditary, and neonatal diseases and abnormalities, Science, Amino Acid Motifs, nutritional and metabolic diseases, Acetylation, Iron Deficiencies, digestive system, Histone Deacetylases, Article, Epigenesis, Genetic, Histones, Mice, Inbred C57BL, Gene Expression Regulation, Hepcidins, hemic and lymphatic diseases, Journal Article, Animals, Humans, lcsh:Q, Promoter Regions, Genetic, lcsh:Science, Erythropoietin
Abstract

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3., Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency.

Published
2017

21. IKZF1 plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric b-cell precursor acute lymphoblastic leukemia

Author

Stanulla, M, Dagdan, E, Zaliova, M, Möricke, A, Palmi, C, Cazzaniga, G, Eckert, C, Te Kronnie, G, Bourquin, J, Bornhauser, B, Koehler, R, Bartram, C, Ludwig, W, Bleckmann, K, Groeneveld-Krentz, S, Schewe, D, Junk, S, Hinze, L, Klein, N, Kratz, C, Biondi, A, Borkhardt, A, Kulozik, A, Muckenthaler, M, Basso, G, Valsecchi, M, Izraeli, S, Petersen, B, Franke, A, Dörge, P, Steinemann, D, Haas, O, Panzer-Grümayer, R, Cavé, H, Houlston, R, Cario, G, Schrappe, M, Zimmermann, M, Stanulla, Martin, Dagdan, Elif, Zaliova, Marketa, Möricke, Anja, Palmi, Chiara, Cazzaniga, Giovanni, Eckert, Cornelia, Te Kronnie, Geertruy, Bourquin, Jean-Pierre, Bornhauser, Beat, Koehler, Rolf, Bartram, Claus R, Ludwig, Wolf-Dieter, Bleckmann, Kirsten, Groeneveld-Krentz, Stefanie, Schewe, Denis, Junk, Stefanie V, Hinze, Laura, Klein, Norman, Kratz, Christian P, Biondi, Andrea, Borkhardt, Arndt, Kulozik, Andreas, Muckenthaler, Martina U, Basso, Giuseppe, Valsecchi, Maria Grazia, Izraeli, Shai, Petersen, Britt-Sabina, Franke, Andre, Dörge, Petra, Steinemann, Doris, Haas, Oskar A, Panzer-Grümayer, Renate, Cavé, Hélène, Houlston, Richard S, Cario, Gunnar, Schrappe, Martin, Zimmermann, Martin, Stanulla, M, Dagdan, E, Zaliova, M, Möricke, A, Palmi, C, Cazzaniga, G, Eckert, C, Te Kronnie, G, Bourquin, J, Bornhauser, B, Koehler, R, Bartram, C, Ludwig, W, Bleckmann, K, Groeneveld-Krentz, S, Schewe, D, Junk, S, Hinze, L, Klein, N, Kratz, C, Biondi, A, Borkhardt, A, Kulozik, A, Muckenthaler, M, Basso, G, Valsecchi, M, Izraeli, S, Petersen, B, Franke, A, Dörge, P, Steinemann, D, Haas, O, Panzer-Grümayer, R, Cavé, H, Houlston, R, Cario, G, Schrappe, M, Zimmermann, M, Stanulla, Martin, Dagdan, Elif, Zaliova, Marketa, Möricke, Anja, Palmi, Chiara, Cazzaniga, Giovanni, Eckert, Cornelia, Te Kronnie, Geertruy, Bourquin, Jean-Pierre, Bornhauser, Beat, Koehler, Rolf, Bartram, Claus R, Ludwig, Wolf-Dieter, Bleckmann, Kirsten, Groeneveld-Krentz, Stefanie, Schewe, Denis, Junk, Stefanie V, Hinze, Laura, Klein, Norman, Kratz, Christian P, Biondi, Andrea, Borkhardt, Arndt, Kulozik, Andreas, Muckenthaler, Martina U, Basso, Giuseppe, Valsecchi, Maria Grazia, Izraeli, Shai, Petersen, Britt-Sabina, Franke, Andre, Dörge, Petra, Steinemann, Doris, Haas, Oskar A, Panzer-Grümayer, Renate, Cavé, Hélène, Houlston, Richard S, Cario, Gunnar, Schrappe, Martin, and Zimmermann, Martin

Abstract

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 6 6% compared with 7965% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion (P ≤.001). Respective 5-year cumulative relapse incidence rates were 44±6%, 11±4%, and 10±1%(P ≤.001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 6 5% versus 40 6 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients (P ≤.001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% (P ≤.001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BF

Published
2018

22. The european hematology association roadmap for european hematology research: A consensus document

Author

Engert, A. Balduini, C. Brand, A. Coiffier, B. Cordonnier, C. Döhner, H. De Wit, T.D. Eichinger, S. Fibbe, W. Green, T. De Haas, F. Iolascon, A. Jaffredo, T. Rodeghiero, F. Sall Es, G. Schuringa, J.J. André, M. Andre-Schmutz, I. Bacigalupo, A. Bochud, P.-Y. Den Boer, M. Bonini, C. Camaschella, C. Cant, A. Cappellini, M.D. Cazzola, M. Celso, C.L. Dimopoulos, M. Douay, L. Dzierzak, E. Einsele, H. Ferreri, A. De Franceschi, L. Gaulard, P. Gottgens, B. Greinacher, A. Gresele, P. Gribben, J. De Haan, G. Hansen, J.-B. Hochhaus, A. Kadir, R. Kaveri, S. Kouskoff, V. Kühne, T. Kyrle, P. Ljungman, P. Maschmeyer, G. Méndez-Ferrer, S. Milsom, M. Mummery, C. Ossenkoppele, G. Pecci, A. Peyvandi, F. Philipsen, S. Reitsma, P. Ribera, J.M. Risitano, A. Rivella, S. Ruf, W. Schroeder, T. Scully, M. Socie, G. Staal, F. Stanworth, S. Stauder, R. Stilgenbauer, S. Tamary, H. Theilgaard-Mönch, K. Thein, S.L. Tilly, H. Trneny, M. Vainchenker, W. Vannucchi, A.M. Viscoli, C. Vrielink, H. Zaaijer, H. Zanella, A. Zolla, L. Zwaginga, J.J. Martinez, P.A. Van Den Akker, E. Allard, S. Anagnou, N. Andolfo, I. Andrau, J.-C. Angelucci, E. Anstee, D. Aurer, I. Avet-Loiseau, H. Aydinok, Y. Bakchoul, T. Balduini, A. Barcellini, W. Baruch, D. Baruchel, A. Bayry, J. Bento, C. Van Den Berg, A. Bernardi, R. Bianchi, P. Bigas, A. Biondi, A. Bohonek, M. Bonnet, D. Borchmann, P. Borregaard, N. Brækkan, S. Van Den Brink, M. Brodin, E. Bullinger, L. Buske, C. Butzeck, B. Cammenga, J. Campo, E. Carbone, A. Cervantes, F. Cesaro, S. Charbord, P. Claas, F. Cohen, H. Conard, J. Coppo, P. Vives Corron, J.-L. Da Costa, L. Davi, F. Delwel, R. Dianzani, I. Domanović, D. Donnelly, P. Drnovšek, T.D. Dreyling, M. Du, M.-Q. Dufour, C. Durand, C. Efremov, D. Eleftheriou, A. Elion, J. Emonts, M. Engelhardt, M. Ezine, S. Falkenburg, F. Favier, R. Federico, M. Fenaux, P. Fitzgibbon, J. Flygare, J. Foà, R. Forrester, L. Galacteros, F. Garagiola, I. Gardiner, C. Garraud, O. Van Geet, C. Geiger, H. Geissler, J. Germing, U. Ghevaert, C. Girelli, D. Godeau, B. Gökbuget, N. Goldschmidt, H. Goodeve, A. Graf, T. Graziadei, G. Griesshammer, M. Gruel, Y. Guilhot, F. Von Gunten, S. Gyssens, I. Halter, J. Harrison, C. Harteveld, C. Hellström-Lindberg, E. Hermine, O. Higgs, D. Hillmen, P. Hirsch, H. Hoskin, P. Huls, G. Inati, A. Johnson, P. Kattamis, A. Kiefel, V. Kleanthous, M. Klump, H. Krause, D. Hovinga, J.K. Lacaud, G. Lacroix-Desmazes, S. Landman-Parker, J. Legouill, S. Lenz, G. Von Lilienfeld-Toal, M. Von Lindern, M. Lopez-Guillermo, A. Lopriore, E. Lozano, M. Macintyre, E. Makris, M. Mannhalter, C. Martens, J. Mathas, S. Matzdorff, A. Medvinsky, A. Menendez, P. Migliaccio, A.R. Miharada, K. Mikulska, M. Minard, V. Montalbán, C. De Montalembert, M. Montserrat, E. Morange, P.-E. Mountford, J. Muckenthaler, M. Müller-Tidow, C. Mumford, A. Nadel, B. Navarro, J.-T. El Nemer, W. Noizat-Pirenne, F. O’Mahony, B. Oldenburg, J. Olsson, M. Oostendorp, R. Palumbo, A. Passamonti, F. Patient, R. De Latour, R.P. Pflumio, F. Pierelli, L. Piga, A. Pollard, D. Raaijmakers, M. Radford, J. Rambach, R. Koneti Rao, A. Raslova, H. Rebulla, P. Rees, D. Ribrag, V. Rijneveld, A. Rinalducci, S. Robak, T. Roberts, I. Rodrigues, C. Rosendaal, F. Rosenwald, A. Rule, S. Russo, R. Saglio, G. Sanchez, M. Scharf, R.E. Schlenke, P. Semple, J. Sierra, J. So-Osman, C. Soria, J.M. Stamatopoulos, K. Stegmayr, B. Stunnenberg, H. Swinkels, D. Barata, J.P.T. Taghon, T. Taher, A. Terpos, E. Thachil, J. Tissot, J.D. Touw, I. Toye, A. Trappe, R. Traverse-Glehen, A. Unal, S. Vaulont, S. Viprakasit, V. Vitolo, U. Van Wijk, R. Wójtowicz, A. Zeerleder, S. Zieger, B. EHA Roadmap for European Hematology Research

Abstract

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at ∈ European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better fu treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. © 2016 Ferrata Storti Foundation.

Published
2016

23. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia

Author

Richter-Pechańska, P, primary, Kunz, J B, additional, Hof, J, additional, Zimmermann, M, additional, Rausch, T, additional, Bandapalli, O R, additional, Orlova, E, additional, Scapinello, G, additional, Sagi, J C, additional, Stanulla, M, additional, Schrappe, M, additional, Cario, G, additional, Kirschner-Schwabe, R, additional, Eckert, C, additional, Benes, V, additional, Korbel, J O, additional, Muckenthaler, M U, additional, and Kulozik, A E, additional

Published
2017
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24. High expression of miR-125b-2 and SNORD116 noncoding RNA clusters characterize ERG-related B cell precursor acute lymphoblastic leukemia

Author

Vendramini, E, Giordan, M, Giarin, E, Michielotto, B, Fazio, G, Cazzaniga, G, Biondi, A, Silvestri, D, Valsecchi, M, Muckenthaler, M, Kulozik, A, Gattei, V, Izraeli, S, Basso, G, Te Kronnie, G, Vendramini, E, Giordan, M, Giarin, E, Michielotto, B, Fazio, G, Cazzaniga, G, Biondi, A, Silvestri, D, Valsecchi, M, Muckenthaler, M, Kulozik, A, Gattei, V, Izraeli, S, Basso, G, and Te Kronnie, G

Abstract

ERG-related leukemia is a B cell precursor acute lymphoblastic leukemia (BCP ALL) subtype characterized by aberrant expression of DUX4 and ERG transcription factors, and highly recurrent ERG intragenic deletions. ERG-related patients have remarkably favorable outcome despite a high incidence of inauspicious IKZF1 aberrations. We describe clinical and genomic features of the ERG-related cases in an unselected cohort of B-other BCP ALL pediatric patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a small noncoding RNA signature specific of ERG-related group, with up-regulation of miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster.

Published
2017

25. The European Hematology Association Roadmap for European Hematology Research: a consensus document.

Author

EHA Roadmap for European Hematology, Research, Engert, A., Balduini, C., Brand, A., Coiffier, B., Cordonnier, C., Döhner, H., de Wit TD., Eichinger, S., Fibbe, W., Green, T., de Haas, F., Iolascon, A., Jaffredo, T., Rodeghiero, F., Salles, G., Schuringa, JJ., André, M., Andre-Schmutz, I., Bacigalupo, A., Bochud, PY., Boer, Md., Bonini, C., Camaschella, C., Cant, A., Cappellini, MD., Cazzola, M., Celso, CL., Dimopoulos, M., Douay, L., Dzierzak, E., Einsele, H., Ferreri, A., De Franceschi, L., Gaulard, P., Gottgens, B., Greinacher, A., Gresele, P., Gribben, J., de Haan, G., Hansen, JB., Hochhaus, A., Kadir, R., Kaveri, S., Kouskoff, V., Kühne, T., Kyrle, P., Ljungman, P., Maschmeyer, G., Méndez-Ferrer£££Simón£££ S., Milsom, M., Mummery, C., Ossenkoppele, G., Pecci, A., Peyvandi, F., Philipsen, S., Reitsma, P., Ribera, JM., Risitano, A., Rivella, S., Ruf, W., Schroeder, T., Scully, M., Socie, G., Staal, F., Stanworth, S., Stauder, R., Stilgenbauer, S., Tamary, H., Theilgaard-Mönch, K., Thein, SL., Tilly, H., Trneny, M., Vainchenker, W., Vannucchi, AM., Viscoli, C., Vrielink, H., Zaaijer, H., Zanella, A., Zolla, L., Zwaginga, JJ., Martinez, PA., van den Akker, E., Allard, S., Anagnou, N., Andolfo, I., Andrau, JC., Angelucci, E., Anstee, D., Aurer, I., Avet-Loiseau, H., Aydinok, Y., Bakchoul, T., Balduini, A., Barcellini, W., Baruch, D., Baruchel, A., Bayry, J., Bento, C., van den Berg, A., Bernardi, R., Bianchi, P., Bigas, A., Biondi, A., Bohonek, M., Bonnet, D., Borchmann, P., Borregaard, N., Brækkan, S., van den Brink, M., Brodin, E., Bullinger, L., Buske, C., Butzeck, B., Cammenga, J., Campo, E., Carbone, A., Cervantes, F., Cesaro, S., Charbord, P., Claas, F., Cohen, H., Conard, J., Coppo, P., Corrons, JL., Costa, Ld., Davi, F., Delwel, R., Dianzani, I., Domanović, D., Donnelly, P., Drnov?ek£££Tadeja Dovč£££ TD., Dreyling, M., Du, MQ., Dufour, C., Durand, C., Efremov, D., Eleftheriou, A., Elion, J., Emonts, M., Engelhardt, M., Ezine, S., Falkenburg, F., Favier, R., Federico, M., Fenaux, P., Fitzgibbon, J., Flygare, J., Foà, R., Forrester, L., Galacteros, F., Garagiola, I., Gardiner, C., Garraud, O., van Geet, C., Geiger, H., Geissler, J., Germing, U., Ghevaert, C., Girelli, D., Godeau, B., Gökbuget, N., Goldschmidt, H., Goodeve, A., Graf, T., Graziadei, G., Griesshammer, M., Gruel, Y., Guilhot, F., von Gunten, S., Gyssens, I., Halter, J., Harrison, C., Harteveld, C., Hellström-Lindberg, E., Hermine, O., Higgs, D., Hillmen, P., Hirsch, H., Hoskin, P., Huls, G., Inati, A., Johnson, P., Kattamis, A., Kiefel, V., Kleanthous, M., Klump, H., Krause, D., Hovinga, JK., Lacaud, G., Lacroix-Desmazes, S., Landman-Parker, J., LeGouill, S., Lenz, G., von Lilienfeld-Toal, M., von Lindern, M., Lopez-Guillermo, A., Lopriore, E., Lozano, M., MacIntyre, E., Makris, M., Mannhalter, C., Martens, J., Mathas, S., Matzdorff, A., Medvinsky, A., Menendez, P., Migliaccio, AR., Miharada, K., Mikulska, M., Minard, V., Montalbán, C., de Montalembert, M., Montserrat, E., Morange, PE., Mountford, J., Muckenthaler, M., Müller-Tidow, C., Mumford, A., Nadel, B., Navarro, JT., Nemer, We., Noizat-Pirenne, F., O'Mahony, B., Oldenburg, J., Olsson, M., Oostendorp, R., Palumbo, A., Passamonti, F., Patient, R., Peffault, R., Pflumio, F., Pierelli, L., Piga, A., Pollard, D., Raaijmakers, M., Radford, J., Rambach, R., Rao, AK., Raslova, H., Rebulla, P., Rees, D., Ribrag, V., Rijneveld, A., Rinalducci, S., Robak, T., Roberts, I., Rodrigues, C., Rosendaal, F., Rosenwald, A., Rule, S., Russo, R., Saglio, G., Sanchez, M., Scharf, RE., Schlenke, P., Semple, J., Sierra, J., So-Osman, C., Soria, JM., Stamatopoulos, K., Stegmayr, B., Stunnenberg, H., Swinkels, D., Barata£££João Pedro Taborda£££ JP., Taghon, T., Taher, A., Terpos, E., Thachil, J., Tissot, JD., Touw, I., Toye, A., Trappe, R., Traverse-Glehen, A., Unal, S., Vaulont, S., Viprakasit, V., Vitolo, U., van Wijk, R., Wójtowicz, A., Zeerleder, S., Zieger, B., de Wit, T.D., Schuringa, J.J., EHA Roadmap for European Hematology, Research, Engert, A., Balduini, C., Brand, A., Coiffier, B., Cordonnier, C., Döhner, H., de Wit TD., Eichinger, S., Fibbe, W., Green, T., de Haas, F., Iolascon, A., Jaffredo, T., Rodeghiero, F., Salles, G., Schuringa, JJ., André, M., Andre-Schmutz, I., Bacigalupo, A., Bochud, PY., Boer, Md., Bonini, C., Camaschella, C., Cant, A., Cappellini, MD., Cazzola, M., Celso, CL., Dimopoulos, M., Douay, L., Dzierzak, E., Einsele, H., Ferreri, A., De Franceschi, L., Gaulard, P., Gottgens, B., Greinacher, A., Gresele, P., Gribben, J., de Haan, G., Hansen, JB., Hochhaus, A., Kadir, R., Kaveri, S., Kouskoff, V., Kühne, T., Kyrle, P., Ljungman, P., Maschmeyer, G., Méndez-Ferrer£££Simón£££ S., Milsom, M., Mummery, C., Ossenkoppele, G., Pecci, A., Peyvandi, F., Philipsen, S., Reitsma, P., Ribera, JM., Risitano, A., Rivella, S., Ruf, W., Schroeder, T., Scully, M., Socie, G., Staal, F., Stanworth, S., Stauder, R., Stilgenbauer, S., Tamary, H., Theilgaard-Mönch, K., Thein, SL., Tilly, H., Trneny, M., Vainchenker, W., Vannucchi, AM., Viscoli, C., Vrielink, H., Zaaijer, H., Zanella, A., Zolla, L., Zwaginga, JJ., Martinez, PA., van den Akker, E., Allard, S., Anagnou, N., Andolfo, I., Andrau, JC., Angelucci, E., Anstee, D., Aurer, I., Avet-Loiseau, H., Aydinok, Y., Bakchoul, T., Balduini, A., Barcellini, W., Baruch, D., Baruchel, A., Bayry, J., Bento, C., van den Berg, A., Bernardi, R., Bianchi, P., Bigas, A., Biondi, A., Bohonek, M., Bonnet, D., Borchmann, P., Borregaard, N., Brækkan, S., van den Brink, M., Brodin, E., Bullinger, L., Buske, C., Butzeck, B., Cammenga, J., Campo, E., Carbone, A., Cervantes, F., Cesaro, S., Charbord, P., Claas, F., Cohen, H., Conard, J., Coppo, P., Corrons, JL., Costa, Ld., Davi, F., Delwel, R., Dianzani, I., Domanović, D., Donnelly, P., Drnov?ek£££Tadeja Dovč£££ TD., Dreyling, M., Du, MQ., Dufour, C., Durand, C., Efremov, D., Eleftheriou, A., Elion, J., Emonts, M., Engelhardt, M., Ezine, S., Falkenburg, F., Favier, R., Federico, M., Fenaux, P., Fitzgibbon, J., Flygare, J., Foà, R., Forrester, L., Galacteros, F., Garagiola, I., Gardiner, C., Garraud, O., van Geet, C., Geiger, H., Geissler, J., Germing, U., Ghevaert, C., Girelli, D., Godeau, B., Gökbuget, N., Goldschmidt, H., Goodeve, A., Graf, T., Graziadei, G., Griesshammer, M., Gruel, Y., Guilhot, F., von Gunten, S., Gyssens, I., Halter, J., Harrison, C., Harteveld, C., Hellström-Lindberg, E., Hermine, O., Higgs, D., Hillmen, P., Hirsch, H., Hoskin, P., Huls, G., Inati, A., Johnson, P., Kattamis, A., Kiefel, V., Kleanthous, M., Klump, H., Krause, D., Hovinga, JK., Lacaud, G., Lacroix-Desmazes, S., Landman-Parker, J., LeGouill, S., Lenz, G., von Lilienfeld-Toal, M., von Lindern, M., Lopez-Guillermo, A., Lopriore, E., Lozano, M., MacIntyre, E., Makris, M., Mannhalter, C., Martens, J., Mathas, S., Matzdorff, A., Medvinsky, A., Menendez, P., Migliaccio, AR., Miharada, K., Mikulska, M., Minard, V., Montalbán, C., de Montalembert, M., Montserrat, E., Morange, PE., Mountford, J., Muckenthaler, M., Müller-Tidow, C., Mumford, A., Nadel, B., Navarro, JT., Nemer, We., Noizat-Pirenne, F., O'Mahony, B., Oldenburg, J., Olsson, M., Oostendorp, R., Palumbo, A., Passamonti, F., Patient, R., Peffault, R., Pflumio, F., Pierelli, L., Piga, A., Pollard, D., Raaijmakers, M., Radford, J., Rambach, R., Rao, AK., Raslova, H., Rebulla, P., Rees, D., Ribrag, V., Rijneveld, A., Rinalducci, S., Robak, T., Roberts, I., Rodrigues, C., Rosendaal, F., Rosenwald, A., Rule, S., Russo, R., Saglio, G., Sanchez, M., Scharf, RE., Schlenke, P., Semple, J., Sierra, J., So-Osman, C., Soria, JM., Stamatopoulos, K., Stegmayr, B., Stunnenberg, H., Swinkels, D., Barata£££João Pedro Taborda£££ JP., Taghon, T., Taher, A., Terpos, E., Thachil, J., Tissot, JD., Touw, I., Toye, A., Trappe, R., Traverse-Glehen, A., Unal, S., Vaulont, S., Viprakasit, V., Vitolo, U., van Wijk, R., Wójtowicz, A., Zeerleder, S., Zieger, B., de Wit, T.D., and Schuringa, J.J.

Abstract

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at euro23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

Published
2016

26. The european hematology association roadmap for european hematology research: A consensus document

Author

Engert, A, Balduini, C, Brand, A, Coiffier, B, Cordonnier, C, Döhner, H, De Wit, T, Eichinger, S, Fibbe, W, Green, T, De Haas, F, Iolascon, A, Jaffredo, T, Rodeghiero, F, Sall Es, G, Schuringa, J, André, M, Andre Schmutz, I, Bacigalupo, A, Bochud, P, Den Boer, M, Bonini, C, Camaschella, C, Cant, A, Cappellini, M, Cazzola, M, Celso, C, Dimopoulos, M, Douay, L, Dzierzak, E, Einsele, H, Ferreri, A, De Franceschi, L, Gaulard, P, Gottgens, B, Greinacher, A, Gresele, P, Gribben, J, De Haan, G, Hansen, J, Hochhaus, A, Kadir, R, Kaveri, S, Kouskoff, V, Kühne, T, Kyrle, P, Ljungman, P, Maschmeyer, G, Méndez Ferrer, S, Milsom, M, Mummery, C, Ossenkoppele, G, Pecci, A, Peyvandi, F, Philipsen, S, Reitsma, P, Ribera, J, Risitano, A, Rivella, S, Ruf, W, Schroeder, T, Scully, M, Socie, G, Staal, F, Stanworth, S, Stauder, R, Stilgenbauer, S, Tamary, H, Theilgaard Mönch, K, Thein, S, Tilly, H, Trneny, M, Vainchenker, W, Vannucchi, A, Viscoli, C, Vrielink, H, Zaaijer, H, Zanella, A, Zolla, L, Zwaginga, J, Martinez, P, Van Den Akker, E, Allard, S, Anagnou, N, Andolfo, I, Andrau, J, Angelucci, E, Anstee, D, Aurer, I, Avet Loiseau, H, Aydinok, Y, Bakchoul, T, Balduini, A, Barcellini, W, Baruch, D, Baruchel, A, Bayry, J, Bento, C, Van Den Berg, A, Bernardi, R, Bianchi, P, Bigas, A, Biondi, A, Bohonek, M, Bonnet, D, Borchmann, P, Borregaard, N, Brækkan, S, Van Den Brink, M, Brodin, E, Bullinger, L, Buske, C, Butzeck, B, Cammenga, J, Campo, E, Carbone, A, Cervantes, F, Cesaro, S, Charbord, P, Claas, F, Cohen, H, Conard, J, Coppo, P, Vives Corron, J, Da Costa, L, Davi, F, Delwel, R, Dianzani, I, Domanović, D, Donnelly, P, Drnovšek, T, Dreyling, M, Du, M, Dufour, C, Durand, C, Efremov, D, Eleftheriou, A, Elion, J, Emonts, M, Engelhardt, M, Ezine, S, Falkenburg, F, Favier, R, Federico, M, Fenaux, P, Fitzgibbon, J, Flygare, J, Foà, R, Forrester, L, Galacteros, F, Garagiola, I, Gardiner, C, Garraud, O, Van Geet, C, Geiger, H, Geissler, J, Germing, U, Ghevaert, C, Girelli, D, Godeau, B, Gökbuget, N, Goldschmidt, H, Goodeve, A, Graf, T, Graziadei, G, Griesshammer, M, Gruel, Y, Guilhot, F, Von Gunten, S, Gyssens, I, Halter, J, Harrison, C, Harteveld, C, Hellström Lindberg, E, Hermine, O, Higgs, D, Hillmen, P, Hirsch, H, Hoskin, P, Huls, G, Inati, A, Johnson, P, Kattamis, A, Kiefel, V, Kleanthous, M, Klump, H, Krause, D, Hovinga, J, Lacaud, G, Lacroix Desmazes, S, Landman Parker, J, Legouill, S, Lenz, G, Von Lilienfeld Toal, M, Von Lindern, M, Lopez Guillermo, A, Lopriore, E, Lozano, M, Macintyre, E, Makris, M, Mannhalter, C, Martens, J, Mathas, S, Matzdorff, A, Medvinsky, A, Menendez, P, Migliaccio, A, Miharada, K, Mikulska, M, Minard, V, Montalbán, C, De Montalembert, M, Montserrat, E, Morange, P, Mountford, J, Muckenthaler, M, Müller Tidow, C, Mumford, A, Nadel, B, Navarro, J, El Nemer, W, Noizat Pirenne, F, O’Mahony, B, Oldenburg, J, Olsson, M, Oostendorp, R, Palumbo, A, Passamonti, F, Patient, R, De Latour, R, Pflumio, F, Pierelli, L, Piga, A, Pollard, D, Raaijmakers, M, Radford, J, Rambach, R, Koneti Rao, A, Raslova, H, Rebulla, P, Rees, D, Ribrag, V, Rijneveld, A, Rinalducci, S, Robak, T, Roberts, I, Rodrigues, C, Rosendaal, F, Rosenwald, A, Rule, S, Russo, R, Saglio, G, Sanchez, M, Scharf, R, Schlenke, P, Semple, J, Sierra, J, So Osman, C, Soria, J, Stamatopoulos, K, Stegmayr, B, Stunnenberg, H, Swinkels, D, Barata, J, Taghon, T, Taher, A, Terpos, E, Thachil, J, Tissot, J, Touw, I, Toye, A, Trappe, R, Traverse Glehen, A, Unal, S, Vaulont, S, Viprakasit, V, Vitolo, U, Van Wijk, R, Wójtowicz, A, Zeerleder, S, Zieger, B, Zieger, B., ZANELLA, ALBERTO, BIONDI, ANDREA, Engert, A, Balduini, C, Brand, A, Coiffier, B, Cordonnier, C, Döhner, H, De Wit, T, Eichinger, S, Fibbe, W, Green, T, De Haas, F, Iolascon, A, Jaffredo, T, Rodeghiero, F, Sall Es, G, Schuringa, J, André, M, Andre Schmutz, I, Bacigalupo, A, Bochud, P, Den Boer, M, Bonini, C, Camaschella, C, Cant, A, Cappellini, M, Cazzola, M, Celso, C, Dimopoulos, M, Douay, L, Dzierzak, E, Einsele, H, Ferreri, A, De Franceschi, L, Gaulard, P, Gottgens, B, Greinacher, A, Gresele, P, Gribben, J, De Haan, G, Hansen, J, Hochhaus, A, Kadir, R, Kaveri, S, Kouskoff, V, Kühne, T, Kyrle, P, Ljungman, P, Maschmeyer, G, Méndez Ferrer, S, Milsom, M, Mummery, C, Ossenkoppele, G, Pecci, A, Peyvandi, F, Philipsen, S, Reitsma, P, Ribera, J, Risitano, A, Rivella, S, Ruf, W, Schroeder, T, Scully, M, Socie, G, Staal, F, Stanworth, S, Stauder, R, Stilgenbauer, S, Tamary, H, Theilgaard Mönch, K, Thein, S, Tilly, H, Trneny, M, Vainchenker, W, Vannucchi, A, Viscoli, C, Vrielink, H, Zaaijer, H, Zanella, A, Zolla, L, Zwaginga, J, Martinez, P, Van Den Akker, E, Allard, S, Anagnou, N, Andolfo, I, Andrau, J, Angelucci, E, Anstee, D, Aurer, I, Avet Loiseau, H, Aydinok, Y, Bakchoul, T, Balduini, A, Barcellini, W, Baruch, D, Baruchel, A, Bayry, J, Bento, C, Van Den Berg, A, Bernardi, R, Bianchi, P, Bigas, A, Biondi, A, Bohonek, M, Bonnet, D, Borchmann, P, Borregaard, N, Brækkan, S, Van Den Brink, M, Brodin, E, Bullinger, L, Buske, C, Butzeck, B, Cammenga, J, Campo, E, Carbone, A, Cervantes, F, Cesaro, S, Charbord, P, Claas, F, Cohen, H, Conard, J, Coppo, P, Vives Corron, J, Da Costa, L, Davi, F, Delwel, R, Dianzani, I, Domanović, D, Donnelly, P, Drnovšek, T, Dreyling, M, Du, M, Dufour, C, Durand, C, Efremov, D, Eleftheriou, A, Elion, J, Emonts, M, Engelhardt, M, Ezine, S, Falkenburg, F, Favier, R, Federico, M, Fenaux, P, Fitzgibbon, J, Flygare, J, Foà, R, Forrester, L, Galacteros, F, Garagiola, I, Gardiner, C, Garraud, O, Van Geet, C, Geiger, H, Geissler, J, Germing, U, Ghevaert, C, Girelli, D, Godeau, B, Gökbuget, N, Goldschmidt, H, Goodeve, A, Graf, T, Graziadei, G, Griesshammer, M, Gruel, Y, Guilhot, F, Von Gunten, S, Gyssens, I, Halter, J, Harrison, C, Harteveld, C, Hellström Lindberg, E, Hermine, O, Higgs, D, Hillmen, P, Hirsch, H, Hoskin, P, Huls, G, Inati, A, Johnson, P, Kattamis, A, Kiefel, V, Kleanthous, M, Klump, H, Krause, D, Hovinga, J, Lacaud, G, Lacroix Desmazes, S, Landman Parker, J, Legouill, S, Lenz, G, Von Lilienfeld Toal, M, Von Lindern, M, Lopez Guillermo, A, Lopriore, E, Lozano, M, Macintyre, E, Makris, M, Mannhalter, C, Martens, J, Mathas, S, Matzdorff, A, Medvinsky, A, Menendez, P, Migliaccio, A, Miharada, K, Mikulska, M, Minard, V, Montalbán, C, De Montalembert, M, Montserrat, E, Morange, P, Mountford, J, Muckenthaler, M, Müller Tidow, C, Mumford, A, Nadel, B, Navarro, J, El Nemer, W, Noizat Pirenne, F, O’Mahony, B, Oldenburg, J, Olsson, M, Oostendorp, R, Palumbo, A, Passamonti, F, Patient, R, De Latour, R, Pflumio, F, Pierelli, L, Piga, A, Pollard, D, Raaijmakers, M, Radford, J, Rambach, R, Koneti Rao, A, Raslova, H, Rebulla, P, Rees, D, Ribrag, V, Rijneveld, A, Rinalducci, S, Robak, T, Roberts, I, Rodrigues, C, Rosendaal, F, Rosenwald, A, Rule, S, Russo, R, Saglio, G, Sanchez, M, Scharf, R, Schlenke, P, Semple, J, Sierra, J, So Osman, C, Soria, J, Stamatopoulos, K, Stegmayr, B, Stunnenberg, H, Swinkels, D, Barata, J, Taghon, T, Taher, A, Terpos, E, Thachil, J, Tissot, J, Touw, I, Toye, A, Trappe, R, Traverse Glehen, A, Unal, S, Vaulont, S, Viprakasit, V, Vitolo, U, Van Wijk, R, Wójtowicz, A, Zeerleder, S, Zieger, B, Zieger, B., ZANELLA, ALBERTO, and BIONDI, ANDREA

Abstract

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at ∈ European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better fu treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

Published
2016

27. CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia

Author

Palmi, C, Savino, A, Silvestri, D, Bronzini, I, Cario, G, Paganin, M, Buldini, B, Galbiati, M, Muckenthaler, M, Bugarin, C, Mina, P, Nagel, S, Barisone, E, Casale, F, Locatelli, F, Nigro, L, Micalizzi, C, Parasole, R, Pession, A, Putti, M, Santoro, N, Testi, A, Ziino, O, Kulozik, A, Zimmermann, M, Schrappe, M, Villa, A, Gaipa, G, Basso, G, Biondi, A, Valsecchi, M, Stanulla, M, Conter, V, Kronnie, G, Cazzaniga, G, PALMI, CHIARA, SAVINO, ANGELA MARIA, VILLA, ANTONELLO, GAIPA, GIUSEPPE, BIONDI, ANDREA, VALSECCHI, MARIA GRAZIA, CONTER, VALENTINO, CAZZANIGA, GIOVANNI ITALO, Palmi, C, Savino, A, Silvestri, D, Bronzini, I, Cario, G, Paganin, M, Buldini, B, Galbiati, M, Muckenthaler, M, Bugarin, C, Mina, P, Nagel, S, Barisone, E, Casale, F, Locatelli, F, Nigro, L, Micalizzi, C, Parasole, R, Pession, A, Putti, M, Santoro, N, Testi, A, Ziino, O, Kulozik, A, Zimmermann, M, Schrappe, M, Villa, A, Gaipa, G, Basso, G, Biondi, A, Valsecchi, M, Stanulla, M, Conter, V, Kronnie, G, Cazzaniga, G, PALMI, CHIARA, SAVINO, ANGELA MARIA, VILLA, ANTONELLO, GAIPA, GIUSEPPE, BIONDI, ANDREA, VALSECCHI, MARIA GRAZIA, CONTER, VALENTINO, and CAZZANIGA, GIOVANNI ITALO

Abstract

Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL. We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers. Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated. Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib. In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.

Published
2016

28. CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia

Author

Palmi, C., Savino, A. M., Silvestri, D., Bronzini, I., Cario, G., Paganin, M., Buldini, B., Galbiati, M., Muckenthaler, M. U., Bugarin, C., Mina, P. D., Nagel, S., Barisone, E., Casale, F., Locatelli, Franco, Nigro, L. L., Micalizzi, C., Parasole, R., Pession, A., Putti, M. C., Santoro, N., Testi, A. M., Ziino, O., Kulozik, A. E., Zimmermann, M., Schrappe, M., Villa, A., Gaipa, G., Basso, G., Biondi, A., Valsecchi, M. G., Stanulla, M., Conter, V., Kronnie, G., Cazzaniga, G., Locatelli F. (ORCID:0000-0002-7976-3654), Palmi, C., Savino, A. M., Silvestri, D., Bronzini, I., Cario, G., Paganin, M., Buldini, B., Galbiati, M., Muckenthaler, M. U., Bugarin, C., Mina, P. D., Nagel, S., Barisone, E., Casale, F., Locatelli, Franco, Nigro, L. L., Micalizzi, C., Parasole, R., Pession, A., Putti, M. C., Santoro, N., Testi, A. M., Ziino, O., Kulozik, A. E., Zimmermann, M., Schrappe, M., Villa, A., Gaipa, G., Basso, G., Biondi, A., Valsecchi, M. G., Stanulla, M., Conter, V., Kronnie, G., Cazzaniga, G., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL. We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers. Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated. Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib. In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.

Published
2016

30. Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation

Author

Jaekel, N, primary, Lieder, K, additional, Albrecht, S, additional, Leismann, O, additional, Hubert, K, additional, Bug, G, additional, Kröger, N, additional, Platzbecker, U, additional, Stadler, M, additional, de Haas, K, additional, Altamura, S, additional, Muckenthaler, M U, additional, Niederwieser, D, additional, and Al-Ali, H K, additional

Published
2015
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31. Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation

Author

Kunz, J. B., primary, Rausch, T., additional, Bandapalli, O. R., additional, Eilers, J., additional, Pechanska, P., additional, Schuessele, S., additional, Assenov, Y., additional, Stutz, A. M., additional, Kirschner-Schwabe, R., additional, Hof, J., additional, Eckert, C., additional, von Stackelberg, A., additional, Schrappe, M., additional, Stanulla, M., additional, Koehler, R., additional, Avigad, S., additional, Elitzur, S., additional, Handgretinger, R., additional, Benes, V., additional, Weischenfeldt, J., additional, Korbel, J. O., additional, Muckenthaler, M. U., additional, and Kulozik, A. E., additional

Published
2015
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33. Eisenüberladung in adulten Hfe-defizienten Mäusen unabhängig von Veränderungen in der Expression der duodenalen Eisentransporter DMT1 und Ireg1/Ferroportin

Author

Herrmann, T, primary, Muckenthaler, M, additional, van der Hoeven, F, additional, Brennan, K, additional, Gehrke, SG, additional, Hubert, N, additional, Sergi, C, additional, Gröne, H-J, additional, Kaiser, I, additional, Gosch, I, additional, Volkmann, M, additional, Riedel, H-D, additional, Hentze, MW, additional, Stewart, AF, additional, and Stremmel, W, additional

Published
2015
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34. Novel activating mutations lacking cysteine in type i cytokine receptors in acute lymphoblastic leukemia

Author

Shochat, C, Tal, N, Gryshkova, V, Birger, Y, Bandapalli, O, Cazzaniga, G, Gershman, N, Kulozik, A, Biondi, A, Mansour, M, Twizere, J, Muckenthaler, M, Ben-Tal, N, Constantinescu, S, Bercovich, D, Izraeli, S, Bandapalli, OR, Kulozik, AE, Mansour, MR, Twizere, JC, Muckenthaler, MU, Constantinescu, SN, Shochat, C, Tal, N, Gryshkova, V, Birger, Y, Bandapalli, O, Cazzaniga, G, Gershman, N, Kulozik, A, Biondi, A, Mansour, M, Twizere, J, Muckenthaler, M, Ben-Tal, N, Constantinescu, S, Bercovich, D, Izraeli, S, Bandapalli, OR, Kulozik, AE, Mansour, MR, Twizere, JC, Muckenthaler, MU, and Constantinescu, SN

Abstract

Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor a (IL7R) or cytokine receptor like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand-independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations

Published
2014

35. miRNAs Affect the Expression of Innate and Adaptive Immunity Proteins in Celiac Disease

Author

Magni, S, BUOLI COMANI, G, Elli, L, Vanessi, S, Ballarini, E, Nicolini, G, Rusconi, M, Castoldi, M, Meneveri, R, Muckenthaler, M, Bardella, M, Barisani, D, Muckenthaler, MU, Bardella, MT, BUOLI COMANI, GAIA, VANESSI, SAMANTA, BALLARINI, ELISA, NICOLINI, GABRIELLA, RUSCONI, MICHELA, MENEVERI, RAFFAELLA, BARISANI, DONATELLA, Magni, S, BUOLI COMANI, G, Elli, L, Vanessi, S, Ballarini, E, Nicolini, G, Rusconi, M, Castoldi, M, Meneveri, R, Muckenthaler, M, Bardella, M, Barisani, D, Muckenthaler, MU, Bardella, MT, BUOLI COMANI, GAIA, VANESSI, SAMANTA, BALLARINI, ELISA, NICOLINI, GABRIELLA, RUSCONI, MICHELA, MENEVERI, RAFFAELLA, and BARISANI, DONATELLA

Abstract

OBJECTIVES: microRNAs (miRNAs) are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNAs could have a role in modulating both innate and adaptive response to gluten in celiac patients. METHODS: We compared miRNA profiles in duodenal biopsies of controls and CD patients by miRNA array. Differentially expressed miRNAs were validated in controls, Marsh 3A-B, and Marsh 3C patients by quantitative PCR (qPCR). Target gene expression was assessed by qPCR, western blotting, and immunohistochemistry, and the effect of gliadin was evaluated by in vitro stimulation experiments on duodenal biopsies. RESULTS: Seven miRNAs were identified as significantly downregulated in the duodenum of adult CD patients as compared with controls. qPCR validated the decreased expression of miR-192-5p, miR-31-5p, miR-338-3p, and miR-197, in particular in patients with more severe histological lesions (Marsh 3C). In silico analysis of possible miRNA targets identified several genes involved in innate and adaptive immunity. Among these, chemokine C-X-C motif ligand 2 (CXCL2) and NOD2 showed significantly increased mRNA and protein level in Marsh 3C patients and a significant inverse correlation with the regulatory miR-192-5p. In addition, forkhead box P3 (FOXP3), Run-related transcription factor 1, and interleukin-18 (targets of miR-31-5p, miR-338-3p, and miR-197, respectively) showed upregulation in CD patients. Furthermore, alterations in CXCL2 and NOD2, FOXP3, miR-192-5p, and miR-31-5p expression were triggered by gliadin exposure in CD patients. CONCLUSIONS: miRNA expression is significantly altered in duodenal mucosa of CD patients, and this alteration can increase the expression of molecules involved in immune response.

Published
2014

36. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse

Author

Bandapalli, O. R., primary, Schuessele, S., additional, Kunz, J. B., additional, Rausch, T., additional, Stutz, A. M., additional, Tal, N., additional, Geron, I., additional, Gershman, N., additional, Izraeli, S., additional, Eilers, J., additional, Vaezipour, N., additional, Kirschner-Schwabe, R., additional, Hof, J., additional, von Stackelberg, A., additional, Schrappe, M., additional, Stanulla, M., additional, Zimmermann, M., additional, Koehler, R., additional, Avigad, S., additional, Handgretinger, R., additional, Frismantas, V., additional, Bourquin, J. P., additional, Bornhauser, B., additional, Korbel, J. O., additional, Muckenthaler, M. U., additional, and Kulozik, A. E., additional

Published
2014
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37. A New Paradigm to Understand and Treat Diabetic Neuropathy

Author

Hidmark, A., additional, Fleming, T., additional, Vittas, S., additional, Mendler, M., additional, Deshpande, D., additional, Groener, J., additional, Müller, B., additional, Reeh, P., additional, Sauer, S., additional, Pham, M., additional, Muckenthaler, M., additional, Bendszus, M., additional, and Nawroth, P., additional

Published
2014
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38. Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome

Author

Cozzi, A, Santambrogio, P, Privitera, D, Broccoli, V, Rotundo, L I, Garavaglia, B, Benz, R, Altamura, S, Goede, J S, Muckenthaler, M U, Levi, S, Cozzi, A, Santambrogio, P, Privitera, D, Broccoli, V, Rotundo, L I, Garavaglia, B, Benz, R, Altamura, S, Goede, J S, Muckenthaler, M U, and Levi, S

Abstract

The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient's fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.

Published
2013

39. High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol

Author

Cario, G., primary, Rhein, P., additional, Mitlohner, R., additional, Zimmermann, M., additional, Bandapalli, O. R., additional, Romey, R., additional, Moericke, A., additional, Ludwig, W.-D., additional, Ratei, R., additional, Muckenthaler, M. U., additional, Kulozik, A. E., additional, Schrappe, M., additional, Stanulla, M., additional, and Karawajew, L., additional

Published
2013
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40. Iron refractory iron deficiency anemia

Author

De Falco, L., primary, Sanchez, M., additional, Silvestri, L., additional, Kannengiesser, C., additional, Muckenthaler, M. U., additional, Iolascon, A., additional, Gouya, L., additional, Camaschella, C., additional, and Beaumont, C., additional

Published
2013
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41. Lack of haptoglobin affects iron transport across duodenum by modulating ferroportin expression

Author

Marro, S, Barisani, D, Chiabrando, D, Fagoonee, S, Muckenthaler, M, Stolte, J, Meneveri, R, Haile, D, Silengo, L, Altruda, F, Tolosano, E, Muckenthaler, MU, Tolosano, E., BARISANI, DONATELLA, MENEVERI, RAFFAELLA, Marro, S, Barisani, D, Chiabrando, D, Fagoonee, S, Muckenthaler, M, Stolte, J, Meneveri, R, Haile, D, Silengo, L, Altruda, F, Tolosano, E, Muckenthaler, MU, Tolosano, E., BARISANI, DONATELLA, and MENEVERI, RAFFAELLA

Abstract

Background & Aims: Haptoglobin is an acute phase protein responsible for the recovery of free hemoglobin from plasma. Haptoglobin-mill mice were previously shown to have an altered heme-iron distribution, thus reproducing what occurs in humans in cases of congenital or acquired anhaptoglobinemia. Here, we report the analysis of iron homeostasis in haptoglobin-mill mice. Methods: Iron absorption was measured in tied-off duodenal segments. Iron stores were evaluated on tissue homogenates and sections. The expression of molecules involved in iron homeostasis was analyzed at the protein and messenger RNA levels both in mice and in murine RAW264.7 macrophages stimulated in vitro with hemoglobin. Results: Analysis of intestinal iron transport reveals that haptoglobin-null mice export significantly more iron from the duodenal mucosa to plasma compared with control counterparts. Increased iron export from the duodenum correlates with increased duodenal expression of ferroportin, both at the protein and messenger RNA levels, whereas hepatic hepcidin expression remains unchanged. Up-regulation of the ferroportin transcript, but not of the protein, also occurs in haptoglobin-null spleen macrophages, which accumulate free hemoglobin-derived iron. Finally, we demonstrate that hemoglobin induces ferroportin expression in RAW264.7 cells. Conclusions: Taking together these data, we suggest that haptoglobin, by controlling plasma levels of hemoglobin, participates in the regulation of ferroportin expression, thus contributing to the regulation of iron transfer from duodenal mucosa to plasma.

Published
2007

42. Regulated poly(A) tail shortening in somatic cells mediated by cap-proximal translational repressor proteins and ribosome association

Author

Muckenthaler M, Gunkel N, Stripecke R, and Matthias Hentze

Subjects
Mammals, RNA Caps, Human Growth Hormone, Iron, Recombinant Proteins, Repressor Proteins, Kinetics, Protein Biosynthesis, Ferritins, Animals, Humans, Poly A, Ribosomes, Research Article
Abstract

The poly(A) tail plays an important role in translation initiation. We report the identification of a mechanism that operates in mammalian somatic cells, and couples mRNA poly(A) tail length with its translation state. The regulation of human ferritin L-chain mRNA by iron-responsive elements (IREs) and iron regulatory proteins (IRPs) is subject to this mechanism: translational repression imposed by IRP binding to the IRE of ferritin L-chain mRNA induces poly(A) tail shortening. For the accumulation of mRNAs with short poly(A) tails, IRP binding to an IRE per se is not sufficient, but must cause translational repression. Interestingly, puromycin and verrucarin (general translation inhibitors that dissociate mRNAs from ribosomes) mimick the negative effect of the specific translational repressor proteins on poly(A) tail length, whereas cycloheximide and anisomycin (general translation inhibitors that maintain the association between mRNAs and ribosomes) preserve long poly(A) tails. Thus, the ribosome association of the mRNA appears to represent the critical determinant. These findings identify a novel mechanism of regulated polyadenylation as a consequence of translational control. They reveal differences in poly(A) tail metabolism between polysomal and mRNP-associated mRNAs. A possible role of this mechanism in the maintenance of translational repression is discussed.

Published
1997

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