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11. The pediatric acute leukemia fusion oncogene ETO2-GLIS2 increases self-renewal and alters differentiation in a human induced pluripotent stem cells-derived model

Author

Bertuccio, S. N., Boudia, F., Cambot, M., Lopez, C. K., Lordier, L., Donada, A., Robert, E., Thirant, C., Aid, Z., Serravalle, S., Astolfi, A., Indio, V., Locatelli, Franco, Pession, A., Vainchenker, W., Masetti, R., Raslova, H., Mercher, T., Locatelli F. (ORCID:0000-0002-7976-3654), Bertuccio, S. N., Boudia, F., Cambot, M., Lopez, C. K., Lordier, L., Donada, A., Robert, E., Thirant, C., Aid, Z., Serravalle, S., Astolfi, A., Indio, V., Locatelli, Franco, Pession, A., Vainchenker, W., Masetti, R., Raslova, H., Mercher, T., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2020

14. PS1498 INCREASED RHOA ACTIVITY DUE TO A DISRUPTED FILAMIN A/ALPHAIIBBETA3 INTERACTION INDUCES MACROTHROMBOCYTOPENIA

Author

Donada, A., primary, Balayn, N., additional, Sliwa, D., additional, Lordier, L., additional, Ceglia, V., additional, Baschieri, F., additional, Goizet, C., additional, Favier, R., additional, Tosca, L., additional, Tachdjian, G., additional, Denis, C., additional, Plo, I., additional, Vainchenker, W., additional, Debili, N., additional, Rosa, J.-P., additional, Bryckaert, M., additional, and Raslova, H., additional

Published
2019
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15. 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

17. 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

18. 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

20. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia

Author

Antony-Debré, I, primary, Duployez, N, additional, Bucci, M, additional, Geffroy, S, additional, Micol, J-B, additional, Renneville, A, additional, Boissel, N, additional, Dhédin, N, additional, Réa, D, additional, Nelken, B, additional, Berthon, C, additional, Leblanc, T, additional, Mozziconacci, M-J, additional, Favier, R, additional, Heller, P G, additional, Abdel-Wahab, O, additional, Raslova, H, additional, Latger-Cannard, V, additional, and Preudhomme, C, additional

Published
2015
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21. Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms

Author

Ali, A, primary, Bluteau, O, additional, Messaoudi, K, additional, Palazzo, A, additional, Boukour, S, additional, Lordier, L, additional, Lecluse, Y, additional, Rameau, P, additional, Kraus-Berthier, L, additional, Jacquet-Bescond, A, additional, Lelièvre, H, additional, Depil, S, additional, Dessen, P, additional, Solary, E, additional, Raslova, H, additional, Vainchenker, W, additional, Plo, I, additional, and Debili, N, additional

Published
2013
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23. p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription.

Author

Buet, D., Raslova, H., Geay, J.-F., Jarrier, P., Lazar, V., Turhan, A., Morlé, F., Vainchenker, W., and Louache, F.

Subjects
*MEGAKARYOCYTE differentiation, *PROTEIN-tyrosine kinases, *CHRONIC myeloid leukemia, *PATHOLOGY, *CELL lines, *CELL culture
Abstract

The BCR-ABL oncoprotein exhibits deregulated protein tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive human leukemias. Here, we report that ectopic expression of p210BCR-ABL in the megakaryoblastic Mo7e cell line and in primary human CD34+ progenitors trigger erythroid differentiation at the expense of megakaryocyte (MK) differentiation. Clonal culture of purified CD41+CD42− cells, a population highly enriched in MK progenitors, combined with the conditional expression of p210BCR-ABL tyrosine kinase activity by imatinib identified a true lineage reprogramming. In both Mo7e or CD41+CD42− cells transduced with p210BCR-ABL, lineage switching was associated with a downregulation of the friend leukemia Integration 1 (FLI-1) transcription factor. Re-expression of FLI-1 in p210BCR-ABL-transduced Mo7e cells rescued the megakaryoblastic phenotype. Altogether, these results demonstrate that alteration of signal transduction via p210BCR-ABL reprograms MK cells into erythroid cells by a downregulation of FLI-1. In addition, our findings underscore the role of kinases in lineage choice and infidelity in pathology and suggest that downregulation of FLI-1 may have important implications in CML pathogenesis.Leukemia (2007) 21, 917–925. doi:10.1038/sj.leu.2404600; published online 22 February 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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26. The European Hematology Association Roadmap for European Hematology Research: a consensus document

Author

Engert, Andreas, Balduini, Carlo, Brand, Anneke, Coiffier, Bertrand, Cordonnier, Catherine, Doehner, Hartmut, de Wit, Thom Duyvene, Eichinger, Sabine, Fibbe, Willem, Green, Tony, de Haas, Fleur, Iolascon, Achille, Jaffredo, Thierry, Rodeghiero, Francesco, Salles, Gilles, Schuringa, Jan Jacob, Andre, Marc, Andre-Schmutz, Isabelle, Bacigalupo, Andrea, Bochud, Pierre-Yves, den Boer, Monique, Bonini, Chiara, Camaschella, Clara, Cant, Andrew, Cappellini, Maria Domenica, Cazzola, Mario, Lo Celso, Cristina, Dimopoulos, Meletios, Douay, Luc, Dzierzak, Elaine, Einsele, Hermann, Ferreri, Andres, De Franceschi, Lucia, Gaulard, Philippe, Gottgens, Berthold, Greinacher, Andreas, Gresele, Paolo, Gribben, John, de Haan, Gerald, Hansen, John-Bjarne, Hochhaus, Andreas, Kadir, Rezan, Kaveri, Srini, Kouskoff, Valerie, Kuehne, Thomas, Kyrle, Paul, Ljungman, Per, Maschmeyer, Georg, Mendez-Ferrer, Simon, Milsom, Michael, Mummery, Christine, Ossenkoppele, Gert, Pecci, Alessandro, Peyvandi, Flora, Philipsen, Sjaak, Reitsma, Pieter, Maria Ribera, Jose, Risitano, Antonio, Rivella, Stefano, Ruf, Wolfram, Schroeder, Timm, Scully, Marie, Socie, Gerard, Staal, Frank, Stanworth, Simon, Stauder, Reinhard, Stilgenbauer, Stephan, Tamary, Hannah, Theilgaard-Monch, Kim, Thein, Swee Lay, Tilly, Herve, Trneny, Marek, Vainchenker, William, Vannucchi, Alessandro Maria, Viscoli, Claudio, Vrielink, Hans, Zaaijer, Hans, Zanella, Alberto, Zolla, Lello, Zwaginga, Jaap Jan, Martinez, Patricia Aguilar, van den Akker, Emile, Allard, Shubha, Anagnou, Nicholas, Andolfo, Immacolata, Andrau, Jean-Christophe, Angelucci, Emanuele, Anstee, David, Aurer, Igor, Avet-Loiseau, Herve, Aydinok, Yesim, Bakchoul, Tamam, Balduini, Alessandra, Barcellini, Wilma, Baruch, Dominique, Baruchel, Andre, Bayry, Jagadeesh, Bento, Celeste, van den Berg, Anke, Bernardi, Rosa, Bianchi, Paola, Bigas, Anna, Biondi, Andrea, Bohonek, Milos, Bonnet, Dominique, Borchmann, Peter, Borregaard, Niels, Braekkan, Sigrid, van den Brink, Marcel, Brodin, Ellen, Bullinger, Lars, Buske, Christian, Butzeck, Barbara, Cammenga, Jorg, Campo, Elias, Carbone, Antonino, Cervantes, Francisco, Cesaro, Simone, Charbord, Pierre, Claas, Frans, Cohen, Hannah, Conard, Jacqueline, Coppo, Paul, Vives Corrons, Joan-Lluis, da Costa, Lydie, Davi, Frederic, Delwel, Ruud, Dianzani, Irma, Domanovic, Dragoslav, Donnelly, Peter, Drnovsek, Tadeja Dovc, Dreyling, Martin, Du, Ming-Qing, Dufour, Carlo, Durand, Charles, Efremov, Dimitar, Eleftheriou, Androulla, Elion, Jacques, Emonts, Marieke, Engelhardt, Monika, Ezine, Sophie, Falkenburg, Fred, Favier, Remi, Federico, Massimo, Fenaux, Pierre, Fitzgibbon, Jude, Flygare, Johan, Foa, Robin, Forrester, Lesley, Galacteros, Frederic, Garagiola, Isabella, Gardiner, Chris, Garraud, Olivier, van Geet, Christel, Geiger, Hartmut, Geissler, Jan, Germing, Ulrich, Ghevaert, Cedric, Girelli, Domenico, Godeau, Bertrand, Goekbuget, Nicola, Goldschmidt, Hartmut, Goodeve, Anne, Graf, Thomas, Graziadei, Giovanna, Griesshammer, Martin, Gruel, Yves, Guilhot, Francois, von Gunten, Stephan, Gyssens, Inge, Halter, Jorg, Harrison, Claire, Harteveld, Cornelis, Hellstrom-Lindberg, Eva, Hermine, Olivier, Higgs, Douglas, Hillmen, Peter, Hirsch, Hans, Hoskin, Peter, Huls, Gerwin, Inati, Adlette, Johnson, Peter, Kattamis, Antonis, Kiefel, Volker, Kleanthous, Marina, Klump, Hannes, Krause, Daniela, Hovinga, Johanna Kremer, Lacaud, Georges, Lacroix-Desmazes, Sebastien, Landman-Parker, Judith, LeGouill, Steven, Lenz, Georg, von Lilienfeld-Toal, Marie, von Lindern, Marieke, Lopez-Guillermo, Armando, Lopriore, Enrico, Lozano, Miguel, MacIntyre, Elizabeth, Makris, Michael, Mannhalter, Christine, Martens, Joost, Mathas, Stephan, Matzdorff, Axel, Medvinsky, Alexander, Menendez, Pablo, Migliaccio, Anna Rita, Miharada, Kenichi, Mikulska, Malgorzata, Minard, Veronique, Montalban, Carlos, de Montalembert, Mariane, Montserrat, Emili, Morange, Pierre-Emmanuel, Mountford, Joanne, Muckenthaler, Martina, Mueller-Tidow, Carsten, Mumford, Andrew, Nadel, Bertrand, Navarro, Jose-Tomas, el Nemer, Wassim, Noizat-Pirenne, France, O'Mahony, Brian, Oldenburg, Johannes, Olsson, Martin, Oostendorp, Robert, Palumbo, Antonio, Passamonti, Francesco, Patient, Roger, de Latour, Regis Peffault, Pflumio, Francoise, Pierelli, Luca, Piga, Antonio, Pollard, Debra, Raaijmakers, Marc, Radford, John, Rambach, Ralf, Rao, A. Koneti, Raslova, Hana, Rebulla, Paolo, Rees, David, Ribrag, Vincent, Rijneveld, Anita, Rinalducci, Sara, Robak, Tadeusz, Roberts, Irene, Rodrigues, Charlene, Rosendaal, Frits, Rosenwald, Andreas, Rule, Simon, Russo, Roberta, Saglio, Guiseppe, Sanchez, Mayka, Scharf, Ruediger E., Schlenke, Peter, Semple, John, Sierra, Jorge, So-Osman, Cynthia, Manuel Soria, Jose, Stamatopoulos, Kostas, Stegmayr, Bernd, Stunnenberg, Henk, Swinkels, Dorine, Taborda Barata, Joao Pedro, Taghon, Tom, Taher, Ali, Terpos, Evangelos, Thachil, Jecko, Tissot, Jean Daniel, Touw, Ivo, Toye, Ash, Trappe, Ralf, Traverse-Glehen, Alexandra, Unal, Sule, Vaulont, Sophie, Viprakasit, Vip, Vitolo, Umberto, van Wijk, Richard, Wojtowicz, Agnieszka, Zeerleder, Sacha, Zieger, Barbara, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of Cologne [Cologne], Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Department of Internal Medicine I, Medizinische Universität Wien = Medical University of Vienna, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ege Üniversitesi, Engert, Andrea, Balduini, Carlo, Brand, Anneke, Coiffier, Bertrand, Cordonnier, Catherine, Döhner, Hartmut, De Wit, Thom Duyvené, Eichinger, Sabine, Fibbe, Willem, Green, Tony, De Haas, Fleur, Iolascon, Achille, Jaffredo, Thierry, Rodeghiero, Francesco, Sall Es, Gille, Schuringa, Jan Jacob, André, Marc, Andre Schmutz, Isabelle, Bacigalupo, Andrea, Bochud, Pierre Yve, Den Boer, Monique, Bonini, Chiara, Camaschella, Clara, Cant, Andrew, Cappellini, Maria Domenica, Cazzola, Mario, Celso, Cristina Lo, Dimopoulos, Meletio, Douay, Luc, Dzierzak, Elaine, Einsele, Hermann, Ferreri, André, De Franceschi, Lucia, Gaulard, Philippe, Gottgens, Berthold, Greinacher, Andrea, Gresele, Paolo, Gribben, John, De Haan, Gerald, Hansen, John Bjarne, Hochhaus, Andrea, Kadir, Rezan, Kaveri, Srini, Kouskoff, Valerie, Kühne, Thoma, Kyrle, Paul, Ljungman, Per, Maschmeyer, Georg, Méndez Ferrer, Simón, Milsom, Michael, Mummery, Christine, Ossenkoppele, Gert, Pecci, Alessandro, Peyvandi, Flora, Philipsen, Sjaak, Reitsma, Pieter, Ribera, José Maria, Risitano, ANTONIO MARIA, Rivella, Stefano, Ruf, Wolfram, Schroeder, Timm, Scully, Marie, Socie, Gerard, Staal, Frank, Stanworth, Simon, Stauder, Reinhard, Stilgenbauer, Stephan, Tamary, Hannah, Theilgaard Mönch, Kim, Thein, Swee Lay, Tilly, Hervé, Trneny, Marek, Vainchenker, William, Vannucchi, Alessandro Maria, Viscoli, Claudio, Vrielink, Han, Zaaijer, Han, Zanella, Alberto, Zolla, Lello, Zwaginga, Jaap Jan, Martinez, Patricia Aguilar, Van Den Akker, Emile, Allard, Shubha, Anagnou, Nichola, Andolfo, Immacolata, Andrau, Jean Christophe, Angelucci, Emanuele, Anstee, David, Aurer, Igor, Avet Loiseau, Hervé, Aydinok, Yesim, Bakchoul, Tamam, Balduini, Alessandra, Barcellini, Wilma, Baruch, Dominique, Baruchel, André, Bayry, Jagadeesh, Bento, Celeste, Van Den Berg, Anke, Bernardi, Rosa, Bianchi, Paola, Bigas, Anna, Biondi, Andrea, Bohonek, Milo, Bonnet, Dominique, Borchmann, Peter, Borregaard, Niel, Brækkan, Sigrid, Van Den Brink, Marcel, Brodin, Ellen, Bullinger, Lar, Buske, Christian, Butzeck, Barbara, Cammenga, Jörg, Campo, Elia, Carbone, Antonino, Cervantes, Francisco, Cesaro, Simone, Charbord, Pierre, Claas, Fran, Cohen, Hannah, Conard, Jacqueline, Coppo, Paul, Vives Corron, Joan Llui, Da Costa, Lydie, Davi, Frederic, Delwel, Ruud, Dianzani, Irma, Domanović, Dragoslav, Donnelly, Peter, Drnovšek, Tadeja Dovč, Dreyling, Martin, Du, Ming Qing, Dufour, Carlo, Durand, Charle, Efremov, Dimitar, Eleftheriou, Androulla, Elion, Jacque, Emonts, Marieke, Engelhardt, Monika, Ezine, Sophie, Falkenburg, Fred, Favier, Remi, Federico, Massimo, Fenaux, Pierre, Fitzgibbon, Jude, Flygare, Johan, Foà, Robin, Forrester, Lesley, Galacteros, Frederic, Garagiola, Isabella, Gardiner, Chri, Garraud, Olivier, Van Geet, Christel, Geiger, Hartmut, Geissler, Jan, Germing, Ulrich, Ghevaert, Cedric, Girelli, Domenico, Godeau, Bertrand, Gökbuget, Nicola, Goldschmidt, Hartmut, Goodeve, Anne, Graf, Thoma, Graziadei, Giovanna, Griesshammer, Martin, Gruel, Yve, Guilhot, Francoi, Von Gunten, Stephan, Gyssens, Inge, Halter, Jörg, Harrison, Claire, Harteveld, Corneli, Hellström Lindberg, Eva, Hermine, Olivier, Higgs, Dougla, Hillmen, Peter, Hirsch, Han, Hoskin, Peter, Huls, Gerwin, Inati, Adlette, Johnson, Peter, Kattamis, Antoni, Kiefel, Volker, Kleanthous, Marina, Klump, Hanne, Krause, Daniela, Hovinga, Johanna Kremer, Lacaud, George, Lacroix Desmazes, Sébastien, Landman Parker, Judith, Legouill, Steven, Lenz, Georg, Von Lilienfeld Toal, Marie, Von Lindern, Marieke, Lopez Guillermo, Armando, Lopriore, Enrico, Lozano, Miguel, Macintyre, Elizabeth, Makris, Michael, Mannhalter, Christine, Martens, Joost, Mathas, Stephan, Matzdorff, Axel, Medvinsky, Alexander, Menendez, Pablo, Migliaccio, Anna Rita, Miharada, Kenichi, Mikulska, Malgorzata, Minard, Véronique, Montalbán, Carlo, De Montalembert, Mariane, Montserrat, Emili, Morange, Pierre Emmanuel, Mountford, Joanne, Muckenthaler, Martina, Müller Tidow, Carsten, Mumford, Andrew, Nadel, Bertrand, Navarro, Jose Toma, El Nemer, Wassim, Noizat Pirenne, France, O’Mahony, Brian, Oldenburg, Johanne, Olsson, Martin, Oostendorp, Robert, Palumbo, Antonio, Passamonti, Francesco, Patient, Roger, De Latour, Regis Peffault, Pflumio, Francoise, Pierelli, Luca, Piga, Antonio, Pollard, Debra, Raaijmakers, Marc, Radford, John, Rambach, Ralf, Koneti Rao, A., Raslova, Hana, Rebulla, Paolo, Rees, David, Ribrag, Vincent, Rijneveld, Anita, Rinalducci, Sara, Robak, Tadeusz, Roberts, Irene, Rodrigues, Charlene, Rosendaal, Frit, Rosenwald, Andrea, Rule, Simon, Russo, Roberta, Saglio, Guiseppe, Sanchez, Mayka, Scharf, Rüdiger E., Schlenke, Peter, Semple, John, Sierra, Jorge, So Osman, Cynthia, Soria, José Manuel, Stamatopoulos, Kosta, Stegmayr, Bernd, Stunnenberg, Henk, Swinkels, Dorine, Barata, João Pedro Taborda, Taghon, Tom, Taher, Ali, Terpos, Evangelo, Thachil, Jecko, Tissot, Jean Daniel, Touw, Ivo, Toye, Ash, Trappe, Ralf, Traverse Glehen, Alexandra, Unal, Sule, Vaulont, Sophie, Viprakasit, Vip, Vitolo, Umberto, Van Wijk, Richard, Wójtowicz, Agnieszka, Zeerleder, Sacha, Zieger, Barbara, Hematology, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of York [York, UK], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pediatrics, Cell biology, Erasmus MC other, Pulmonary Medicine, Medical Oncology, Other departments, AII - Amsterdam institute for Infection and Immunity, Medical Microbiology and Infection Prevention, ACS - Amsterdam Cardiovascular Sciences, Clinical Haematology, 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, and the other authors of the EHA Roadmap for European Hematology, Research, Cancer Research UK, Biotechnology and Biological Sciences Research Council (BBSRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), De Wit, T, De Haas, 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, Andreas Engert, Carlo Balduini, Anneke Brand, Bertrand Coiffier, Catherine Cordonnier, Hartmut Döhner, Thom Duyvené de Wit, Sabine Eichinger, Willem Fibbe, Tony Green, Fleur de Haas, Achille Iolascon, Thierry Jaffredo, Francesco Rodeghiero, Gilles Salles, Jan Jacob Schuringa, the other authors of the EHA Roadmap for European Hematology Research, Anna Rita Migliaccio, 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., Stem Cell Aging Leukemia and Lymphoma (SALL), and Çocuk Sağlığı ve Hastalıkları

Subjects
0301 basic medicine, Cancer Research, diagnosis, Health Services for the Aged, ACUTE PROMYELOCYTIC LEUKEMIA, Medizin, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, EHA Roadmap for European Hematology Research, Antineoplastic Agent, 0302 clinical medicine, European Hematology Association Roadmap, Germany, PERIPHERAL T-CELL, Medicine and Health Sciences, Hematopoiesi, genetics, Molecular Targeted Therapy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, ComputingMilieux_MISCELLANEOUS, Hematology, Genome, Hematopoietic Stem Cell Transplantation, Anemia, Awareness, Supply & distribution, Combined Modality Therapy, 3. Good health, Europe, THROMBOPOIETIN-RECEPTOR AGONISTS, Blood Disorder, Italy, Austria, haematology, Medicine, France, Immunotherapy, Infection, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Human, medicine.medical_specialty, Thrombopoietin Receptor Agonists, Consensus, Patients, Immunology, Antineoplastic Agents, Blood Coagulation, Gene Expression Profiling, Genetic Therapy, Genome, Human, Hematologic Diseases, Hematopoiesis, Humans, Consensu, [SDV.CAN]Life Sciences [q-bio]/Cancer, ACUTE MYELOID-LEUKEMIA, 1102 Cardiovascular Medicine And Haematology, Genetic therapy, methods, 03 medical and health sciences, blood, Internal medicine, medicine, Hematologi, THROMBOTIC THROMBOCYTOPENIC PURPURA, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ACUTE LYMPHOBLASTIC-LEUKEMIA, therapy, business.industry, CHRONIC LYMPHOCYTIC-LEUKEMIA, supply & distribution, STEM-CELL TRANSPLANTATION, economics, Hematologic Disease, Opinion Article, Transplantation, 030104 developmental biology, Family medicine, therapeutic use, drug effects, RANDOMIZED-CONTROLLED-TRIAL, HEMOLYTIC-UREMIC SYNDROME, pathology, business, chemical synthesis, 030215 immunology, Stem Cell Transplantation, transplantation
Abstract

WOS: 000379156300012, PubMed ID: 26819058, 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 (sic)23 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., Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [BB/L023776/1, BB/I00050X/1, BB/K021168/1]; Cancer Research UKCancer Research UK [11831]; Medical Research CouncilMedical Research Council UK (MRC) [G1000801a]; Novo Nordisk FondenNovo Nordisk [NNF12OC1015986]; British Heart FoundationBritish Heart Foundation [FS/09/039/27788]; Cancer Research UKCancer Research UK [12765]; Medical Research CouncilMedical Research Council UK (MRC) [MR/L022982/1, MC_UU_12009/8, MC_U137981013, MC_PC_12009]

Published
2016

27. The pediatric acute leukemia fusion oncogene ETO2-GLIS2 increases self-renewal and alters differentiation in a human induced pluripotent stem cells-derived model

Author

Franco Locatelli, Salvatore Serravalle, Cécile Thirant, Andrea Pession, Riccardo Masetti, Annalisa Astolfi, William Vainchenker, Valentina Indio, Alessandro Donada, Zakia Aid, Thomas Mercher, Salvatore Nicola Bertuccio, Elie Robert, Hana Raslova, Fabien Boudia, Larissa Lordier, Cécile K. Lopez, Marie Cambot, Bertuccio, SN, Boudia, F, Cambot, M, Lopez, CK, Lordier, L, Donada, A, Robert, E, Thirant, C, Aid, Z, Serravalle, S, Astolfi, A, Indio, V, Locatelli, F, Pession, A, Vainchenker, W, Masetti, R, Raslova, H, and Mercher, T

Subjects
Letter, Biology, Self renewal, NO, 03 medical and health sciences, 0302 clinical medicine, Text mining, GLIS2, Human Induced Pluripotent Stem Cells, 030304 developmental biology, 0303 health sciences, Acute leukemia, Oncogene, lcsh:RC633-647.5, business.industry, lcsh:Diseases of the blood and blood-forming organs, Hematology, 3. Good health, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ETO2-GLIS2, Cancer research, na, business
Abstract

Supplemental Digital Content is available in the text.

Published
2020

28. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation

Author

Paquita Nurden, Eric Solary, William Vainchenker, Hana Raslova, Silverio Perrotta, Alessandra Balduini, Patrizia Noris, Guy Leverger, Najet Debili, Nathalie Balayn, Rémi Favier, Caroline Deswarte, Dominique Bluteau, Manuela Currao, Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Pavia, Hôpital Xavier Arnozan, CHU Bordeaux [Bordeaux]-Hôpital Xavier Arnozan, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Second University of Naples-Caserta, University of Naples Federico II, École Pratique des Hautes Études (EPHE), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Naples Federico II = Università degli studi di Napoli Federico II, Bluteau, D, Balduini, A, Balayn, N, Currao, M, Nurden, P, Deswarte, C, Leverger, G, Noris, P, Perrotta, Silverio, Solary, E, Vainchenker, W, Debili, N, Favier, R, Raslova, H., and HAL UPMC, Gestionnaire

Subjects
MAPK/ERK pathway, Male, Friend leukemia, Chromosome Disorders, chemistry.chemical_compound, hemic and lymphatic diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Nuclear Proteins, Cell Differentiation, Chromosome Breakage, General Medicine, Middle Aged, 3. Good health, Pedigree, Leukemia, RUNX1, FLI1, Core Binding Factor Alpha 2 Subunit, Intercellular Signaling Peptides and Proteins, Female, Chromosome breakage, Megakaryocytes, Receptors, Thrombopoietin, Research Article, Signal Transduction, Adult, Adolescent, MAP Kinase Signaling System, Molecular Sequence Data, Biology, Young Adult, medicine, Humans, Gene Silencing, Transcription factor, Thrombopoietin, Binding Sites, Base Sequence, Proto-Oncogene Protein c-fli-1, Infant, medicine.disease, Molecular biology, Thrombocytopenia, Enzyme Activation, chemistry, Gene Expression Regulation, Mutation, Cancer research, 5' Untranslated Regions, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Point mutations in the 5′ UTR of ankyrin repeat domain 26 (ANKRD26) are associated with familial throm-bocytopenia 2 (THC2) and a predisposition to leukemia. Here, we identified underlying mechanisms of ANKRD26-associated thrombocytopenia. Using megakaryocytes (MK) isolated from THC2 patients and healthy subjects, we demonstrated that THC2-associated mutations in the 5′ UTR of ANKRD26 resulted in loss of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 transcription factor (FLI1) binding. RUNX1 and FLI1 binding at the 5′ UTR from healthy subjects led to ANKRD26 silencing during the late stages of megakaryopoiesis and blood platelet development. We showed that persistent ANKRD26 expression in isolated MKs increased signaling via the thrombopoietin/myeloproliferative leukemia virus oncogene (MPL) pathway and impaired proplatelet formation by MKs. Importantly, we demonstrated that ERK inhibition completely rescued the in vitro proplatelet formation defect. Our data identify a mechanism for development of the familial thrombocytopenia THC2 that is related to abnormal MAPK signaling.

Published
2014

29. DiPRO1 distinctly reprograms muscle and mesenchymal cancer cells.

Author

Rich J, Bennaroch M, Notel L, Patalakh P, Alberola J, Issa F, Opolon P, Bawa O, Rondof W, Marchais A, Dessen P, Meurice G, Le-Gall M, Polrot M, Ser-Le Roux K, Mamchaoui K, Droin N, Raslova H, Maire P, Geoerger B, and Pirozhkova I

Subjects
Humans, Cell Proliferation, Myoblasts metabolism, Cell Differentiation
Abstract

We have recently identified the uncharacterized ZNF555 protein as a component of a productive complex involved in the morbid function of the 4qA locus in facioscapulohumeral dystrophy. Subsequently named DiPRO1 (Death, Differentiation, and PROliferation related PROtein 1), our study provides substantial evidence of its role in the differentiation and proliferation of human myoblasts. DiPRO1 operates through the regulatory binding regions of SIX1, a master regulator of myogenesis. Its relevance extends to mesenchymal tumors, such as rhabdomyosarcoma (RMS) and Ewing sarcoma, where DiPRO1 acts as a repressor via the epigenetic regulators TIF1B and UHRF1, maintaining methylation of cis-regulatory elements and gene promoters. Loss of DiPRO1 mimics the host defense response to virus, awakening retrotransposable repeats and the ZNF/KZFP gene family. This enables the eradication of cancer cells, reprogramming the cellular decision balance towards inflammation and/or apoptosis by controlling TNF-α via NF-kappaB signaling. Finally, our results highlight the vulnerability of mesenchymal cancer tumors to si/shDiPRO1-based nanomedicines, positioning DiPRO1 as a potential therapeutic target., (© 2024. The Author(s).)

Published
2024
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30. Deregulation of the p19/CDK4/CDK6 axis in Jak2 V617F megakaryocytes accelerates the development of myelofibrosis.

Author

Duparc H, Muller D, Gilles L, Chédeville AL, El Khoury M, Guignard R, Debili N, Wittner M, Kauskot A, Pasquier F, Antony-Debré I, Marty C, Vainchenker W, Plo I, and Raslova H

Subjects
Humans, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 6 genetics, Janus Kinase 2 genetics, Megakaryocytes, Myeloproliferative Disorders, Primary Myelofibrosis genetics
Published
2024
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31. Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Author

Homan CC, Drazer MW, Yu K, Lawrence DM, Feng J, Arriola-Martinez L, Pozsgai MJ, McNeely KE, Ha T, Venugopal P, Arts P, King-Smith SL, Cheah J, Armstrong M, Wang P, Bödör C, Cantor AB, Cazzola M, Degelman E, DiNardo CD, Duployez N, Favier R, Fröhling S, Rio-Machin A, Klco JM, Krämer A, Kurokawa M, Lee J, Malcovati L, Morgan NV, Natsoulis G, Owen C, Patel KP, Preudhomme C, Raslova H, Rienhoff H, Ripperger T, Schulte R, Tawana K, Velloso E, Yan B, Kim E, Sood R, Hsu AP, Holland SM, Phillips K, Poplawski NK, Babic M, Wei AH, Forsyth C, Mar Fan H, Lewis ID, Cooney J, Susman R, Fox LC, Blombery P, Singhal D, Hiwase D, Phipson B, Schreiber AW, Hahn CN, Scott HS, Liu P, Godley LA, and Brown AL

Subjects
Humans, Core Binding Factor Alpha 2 Subunit genetics, Germ-Line Mutation, DEAD-box RNA Helicases genetics, Carcinogenesis, Germ Cells, GATA2 Transcription Factor genetics, Hematologic Neoplasms genetics, Leukemia
Abstract

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Published
2023
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32. ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis.

Author

Basso-Valentina F, Donada A, Manchev VT, Lisetto M, Balayn N, Martin JE, Muller D, Oyarzun CPM, Duparc H, Arkoun B, Cumin A, Faivre L, Droin N, Biunno I, Pecci A, Balduini A, Debili N, Antony-Debré I, Marty C, Vainchenker W, Plo I, Favier R, and Raslova H

Subjects
Humans, Cytokines, Hematopoiesis, Cell Differentiation, Intercellular Signaling Peptides and Proteins, Receptors, Cytokine, Leukemia pathology
Abstract

Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes thrombocytopenia 2 (THC2), an inherited platelet disorder associated with a predisposition to leukemia. Some patients also present with erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patients' cells and patient-derived induced pluripotent stem cells) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor cell proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly affects the proliferation/differentiation balance for the three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization that leads to increased signaling and cytokine hypersensitivity. These findings afford evidence how ANKRD26 overexpression or the absence of its silencing during differentiation is responsible for myeloid blood cell abnormalities in patients with THC2.

Published
2023
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33. A gain-of-function filamin A mutation in mouse platelets induces thrombus instability.

Author

Adam F, Kauskot A, Lamrani L, Solarz J, Soukaseum C, Repérant C, Denis CV, Raslova H, Rosa JP, and Bryckaert M

Subjects
Male, Female, Mice, Animals, Filamins genetics, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Gain of Function Mutation, Mutation, Thrombosis genetics, Thrombosis metabolism, Hemostatics
Abstract

Background: Filaminopathies A are rare disorders affecting the brain, intestine, or skeleton, characterized by dominant X-linked filamin A (FLNA) gene mutations. Macrothrombocytopenia with functionally defective platelets is frequent. We have described a filaminopathy A male patient, exhibiting a C-terminal frame-shift FLNa mutation (Berrou et al., Arterioscler Thromb Vasc Biol. 2017;37:1087-1097). Contrasting with female patients, this male patient exhibited gain of platelet functions, including increased platelet aggregation, integrin αIIbβ3 activation, and secretion at low agonist concentration, raising the issue of thrombosis risk., Objectives: Our goal is to assess the thrombotic potential of the patient FLNa mutation in an in vivo model., Methods: We have established a mutant FlnA knock-in mouse model., Results: The mutant FlnA mouse platelets phenocopied patient platelets, showing normal platelet count, lower expression level of mutant FlnA, and gain of platelet functions: increased platelet aggregation, secretion, and αIIbβ3 activation, as well as increased spreading and clot retraction. Surprisingly, mutant FlnA mice exhibited a normal bleeding time, but with increased re-bleeding (77%) compared to wild type (WT) FlnA mice (27%), reflecting hemostatic plug instability. Again, in an in vivo thrombosis model, the occlusion time was not altered by the FlnA mutation, but arteriolar embolies were increased (7-fold more frequent in mutant FlnA mice versus WT mice), confirming thrombus instability., Conclusions: This study shows that the FlnA mutation found in the male patient induced gain of platelet functions in vitro, but thrombus instability in vivo. Implications for the role of FLNa in physiology of thrombus formation are discussed., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Published
2022
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34. Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model.

Author

Arkoun B, Robert E, Boudia F, Mazzi S, Dufour V, Siret A, Mammasse Y, Aid Z, Vieira M, Imanci A, Aglave M, Cambot M, Petermann R, Souquere S, Rameau P, Catelain C, Diot R, Tachdjian G, Hermine O, Droin N, Debili N, Plo I, Malinge S, Soler E, Raslova H, Mercher T, and Vainchenker W

Subjects
Cell Cycle Proteins genetics, Child, Chondroitin Sulfate Proteoglycans genetics, Chromosomal Proteins, Non-Histone genetics, GATA1 Transcription Factor genetics, Hematopoiesis, Humans, Megakaryocytes metabolism, Mutation, Trisomy, Down Syndrome genetics, Leukemia, Megakaryoblastic, Acute complications, Leukemia, Megakaryoblastic, Acute genetics, Leukemia, Megakaryoblastic, Acute metabolism
Abstract

Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/-, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations. Transcriptional, chromatin accessibility, and GATA1-binding data showed alteration of essential megakaryocyte differentiation genes, including NFE2 downregulation that was associated with loss of GATA1s binding and functionally involved in megakaryocyte differentiation blockage. T21 enhanced the proliferative phenotype, reproducing the cellular and molecular abnormalities of DS-AMKL. Our study provides an array of human cell-based models revealing individual contributions of different mutations to DS-AMKL differentiation blockage, a major determinant of leukemic progression.

Published
2022
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35. An inherited gain-of-function risk allele in EPOR predisposes to familial JAK2 V617F myeloproliferative neoplasms.

Author

Rabadan Moraes G, Pasquier F, Marzac C, Deconinck E, Damanti CC, Leroy G, El-Khoury M, El Nemer W, Kiladjian JJ, Raslova H, Najman A, Vainchenker W, Marty C, Bellanné-Chantelot C, and Plo I

Subjects
Alleles, Gain of Function Mutation, Humans, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mutation, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Polycythemia Vera genetics, Receptors, Erythropoietin genetics, Thrombocythemia, Essential genetics
Abstract

Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPOR P488S ) in a large family diagnosed with JAK2 V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2 V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPOR P488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Published
2022
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36. New insights into regulation of αIIbβ3 integrin signaling by filamin A.

Author

Lamrani L, Adam F, Soukaseum C, Denis CV, Raslova H, Rosa JP, and Bryckaert M

Abstract

Background: Filamin (FLN) regulates many cell functions through its scaffolding activity cross-linking cytoskeleton and integrins. FLN was shown to inhibit integrin activity, but the exact mechanism remains unclear., Objectives: The aim of this study was to evaluate the role of filamin A (FLNa) subdomains on the regulation of integrin αIIbβ3 signaling., Methods: Three FLNa deletion mutants were overexpressed in the erythro-megakaryocytic leukemic cell line HEL: Del1, which lacks the N-terminal CH1-CH2 domains mediating the FLNa-actin interaction; Del2, lacking the Ig-like repeat 21, which mediates the FLNa-β3 interaction; and Del3, lacking the C-terminal Ig repeat 24, responsible for FLNa dimerization and interaction with the small Rho guanosine triphosphatase involved in actin cytoskeleton reorganisation. Fibrinogen binding to HEL cells in suspension and talin-β3 proximity in cells adherent to immobilized fibrinogen were assessed before and after αIIbβ3 activation by the protein kinase C agonist phorbol 12-myristate 13-acetate., Results: Our results show that FLNa-actin and FLNa-β3 interactions negatively regulate αIIbβ3 activation. Moreover, FLNa-actin interaction represses Rac activation, contributing to the negative regulation of αIIbβ3 activation. In contrast, the FLNa dimerization domain, which maintains Rho inactive, was found to negatively regulate αIIbβ3 outside-in signaling., Conclusion: We conclude that FLNa negatively controls αIIbβ3 activation by regulating actin polymerization and restraining activation of Rac, as well as outside-in signaling by repressing Rho., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Published
2022
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37. ETV6-RUNX1 and RUNX1 directly regulate RAG1 expression: one more step in the understanding of childhood B-cell acute lymphoblastic leukemia leukemogenesis.

Author

Jakobczyk H, Jiang Y, Debaize L, Soubise B, Avner S, Sérandour AA, Rouger-Gaudichon J, Rio AG, Carroll JS, Raslova H, Gilot D, Liu Z, Demengeot J, Salbert G, Douet-Guilbert N, Corcos L, Galibert MD, Gandemer V, and Troadec MB

Subjects
Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Core Binding Factor Alpha 2 Subunit genetics, Homeodomain Proteins genetics, Humans, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Tumor Cells, Cultured, Cell Transformation, Neoplastic pathology, Core Binding Factor Alpha 2 Subunit metabolism, Gene Expression Regulation, Leukemic, Homeodomain Proteins metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Published
2022
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38. Lyl-1 regulates primitive macrophages and microglia development.

Author

Wang S, Ren D, Arkoun B, Kaushik AL, Matherat G, Lécluse Y, Filipp D, Vainchenker W, Raslova H, Plo I, and Godin I

Subjects
Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Female, Mice embryology, Neoplasm Proteins metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Macrophages metabolism, Microglia metabolism, Neoplasm Proteins genetics, Yolk Sac metabolism
Abstract

During ontogeny, macrophage populations emerge in the Yolk Sac (YS) via two distinct progenitor waves, prior to hematopoietic stem cell development. Macrophage progenitors from the primitive/"early EMP" and transient-definitive/"late EMP" waves both contribute to various resident primitive macrophage populations in the developing embryonic organs. Identifying factors that modulates early stages of macrophage progenitor development may lead to a better understanding of defective function of specific resident macrophage subsets. Here we show that YS primitive macrophage progenitors express Lyl-1, a bHLH transcription factor related to SCL/Tal-1. Transcriptomic analysis of YS macrophage progenitors indicate that primitive macrophage progenitors present at embryonic day 9 are clearly distinct from those present at later stages. Disruption of Lyl-1 basic helix-loop-helix domain leads initially to an increased emergence of primitive macrophage progenitors, and later to their defective differentiation. These defects are associated with a disrupted expression of gene sets related to embryonic patterning and neurodevelopment. Lyl-1-deficiency also induce a reduced production of mature macrophages/microglia in the early brain, as well as a transient reduction of the microglia pool at midgestation and in the newborn. We thus identify Lyl-1 as a critical regulator of primitive macrophages and microglia development, which disruption may impair resident-macrophage function during organogenesis., (© 2021. The Author(s).)

Published
2021
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39. Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms.

Author

Mosca M, Hermange G, Tisserand A, Noble R, Marzac C, Marty C, Le Sueur C, Campario H, Vertenoeil G, El-Khoury M, Catelain C, Rameau P, Gella C, Lenglet J, Casadevall N, Favier R, Solary E, Cassinat B, Kiladjian JJ, Constantinescu SN, Pasquier F, Hochberg ME, Raslova H, Villeval JL, Girodon F, Vainchenker W, Cournède PH, and Plo I

Subjects
Calreticulin genetics, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells pathology, Humans, Immunologic Factors pharmacology, Interferon-alpha pharmacology, Janus Kinase 2 genetics, Longitudinal Studies, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology, Prospective Studies, Receptors, Thrombopoietin genetics, Tumor Cells, Cultured, Hematopoietic Stem Cells drug effects, Immunologic Factors therapeutic use, Interferon-alpha therapeutic use, Mutation drug effects, Myeloproliferative Disorders drug therapy
Abstract

Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose., (© 2021 by The American Society of Hematology.)

Published
2021
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40. The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy.

Author

Homan CC, King-Smith SL, Lawrence DM, Arts P, Feng J, Andrews J, Armstrong M, Ha T, Dobbins J, Drazer MW, Yu K, Bödör C, Cantor A, Cazzola M, Degelman E, DiNardo CD, Duployez N, Favier R, Fröhling S, Fitzgibbon J, Klco JM, Krämer A, Kurokawa M, Lee J, Malcovati L, Morgan NV, Natsoulis G, Owen C, Patel KP, Preudhomme C, Raslova H, Rienhoff H, Ripperger T, Schulte R, Tawana K, Velloso E, Yan B, Liu P, Godley LA, Schreiber AW, Hahn CN, Scott HS, and Brown AL

Subjects
Core Binding Factor Alpha 2 Subunit genetics, Genomics, Humans, Registries, Blood Platelet Disorders genetics, Blood Platelet Disorders pathology, Leukemia, Myeloid, Acute, Neoplasms
Published
2021
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41. Dual role of EZH2 in megakaryocyte differentiation.

Author

Mazzi S, Dessen P, Vieira M, Dufour V, Cambot M, El Khoury M, Antony-Debré I, Arkoun B, Basso-Valentina F, BenAbdoulahab S, Edmond V, Rameau P, Petermann R, Wittner M, Cassinat B, Plo I, Debili N, Raslova H, and Vainchenker W

Subjects
Animals, Blood Platelets cytology, Blood Platelets metabolism, Cells, Cultured, Enhancer of Zeste Homolog 2 Protein genetics, Humans, Megakaryocytes metabolism, Mice, RNA Interference, Transcriptome, Enhancer of Zeste Homolog 2 Protein metabolism, Megakaryocytes cytology, Thrombopoiesis
Abstract

EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and polyploidization and decreases proplatelet formation. EZH2 inhibitors similarly reduce MK polyploidization and proplatelet formation in vitro and platelet levels in vivo in a JAK2V617F background. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression of genes involved in DNA replication and repair and an upregulation of cyclin-dependent kinase inhibitors, particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and to a lesser extent CDKN2D could partially rescue the percentage of polyploid MKs. Moreover, H3K27me3 and EZH2 chromatin immunoprecipitation assays revealed that CDKN1A is a direct EZH2 target and CDKN2D expression is not directly regulated by EZH2, suggesting that EZH2 controls MK polyploidization directly through CDKN1A and indirectly through CDKN2D., (© 2021 by The American Society of Hematology.)

Published
2021
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43. Role of Rho-GTPases in megakaryopoiesis.

Author

Vainchenker W, Arkoun B, Basso-Valentina F, Lordier L, Debili N, and Raslova H

Subjects
Animals, Blood Platelets enzymology, Cytoskeleton enzymology, Humans, Megakaryocytes enzymology, Signal Transduction, Blood Platelets physiology, Cytoskeleton physiology, Megakaryocytes physiology, rho GTP-Binding Proteins metabolism
Abstract

Megakaryocytes (MKs) are the bone marrow (BM) cells that generate blood platelets by a process that requires: i) polyploidization responsible for the increased MK size and ii) cytoplasmic organization leading to extension of long pseudopods, called proplatelets, through the endothelial barrier to allow platelet release into blood. Low level of localized RHOA activation prevents actomyosin accumulation at the cleavage furrow and participates in MK polyploidization. In the platelet production, RHOA and CDC42 play opposite, but complementary roles. RHOA inhibits both proplatelet formation and MK exit from BM, whereas CDC42 drives the development of the demarcation membranes and MK migration in BM. Moreover, the RhoA or Cdc42 MK specific knock-out in mice and the genetic alterations in their down-stream effectors in human induce a thrombocytopenia demonstrating their key roles in platelet production. A better knowledge of Rho-GTPase signalling is thus necessary to develop therapies for diseases associated with platelet production defects. Abbreviations: AKT: Protein Kinase BARHGEF2: Rho/Rac Guanine Nucleotide Exchange Factor 2ARP2/3: Actin related protein 2/3BM: Bone marrowCDC42: Cell division control protein 42 homologCFU-MK: Colony-forming-unit megakaryocyteCIP4: Cdc42-interacting protein 4mDIA: DiaphanousDIAPH1; Protein diaphanous homolog 1ECT2: Epithelial Cell Transforming Sequence 2FLNA: Filamin AGAP: GTPase-activating proteins or GTPase-accelerating proteinsGDI: GDP Dissociation InhibitorGEF: Guanine nucleotide exchange factorHDAC: Histone deacetylaseLIMK: LIM KinaseMAL: Megakaryoblastic leukaemiaMARCKS: Myristoylated alanine-rich C-kinase substrateMKL: Megakaryoblastic leukaemiaMLC: Myosin light chainMRTF: Myocardin Related Transcription FactorOTT: One-Twenty Two ProteinPACSIN2: Protein Kinase C And Casein Kinase Substrate In Neurons 2PAK: P21-Activated KinasePDK: Pyruvate Dehydrogenase kinasePI3K: Phosphoinositide 3-kinasePKC: Protein kinase CPTPRJ: Protein tyrosine phosphatase receptor type JRAC: Ras-related C3 botulinum toxin substrate 1RBM15: RNA Binding Motif Protein 15RHO: Ras homologousROCK: Rho-associated protein kinaseSCAR: Suppressor of cAMP receptorSRF: Serum response factorSRC: SarcTAZ: Transcriptional coactivator with PDZ motifTUBB1: Tubulin β1VEGF: Vascular endothelial growth factorWAS: Wiskott Aldrich syndromeWASP: Wiskott Aldrich syndrome proteinWAVE: WASP-family verprolin-homologous proteinWIP: WASP-interacting proteinYAP: Yes-associated protein.

Published
2021
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44. CALR mutant protein rescues the response of MPL p.R464G variant associated with CAMT to eltrombopag.

Author

Basso-Valentina F, Levy G, Varghese LN, Oufadem M, Neven B, Boussard C, Balayn N, Marty C, Vainchenker W, Plo I, Ballerini P, Constantinescu SN, Favier R, and Raslova H

Subjects
Adult, Amino Acid Substitution, Child, Child, Preschool, Female, HEK293 Cells, Homozygote, Humans, Infant, Male, Benzoates pharmacology, Calreticulin genetics, Calreticulin metabolism, Congenital Bone Marrow Failure Syndromes drug therapy, Congenital Bone Marrow Failure Syndromes genetics, Congenital Bone Marrow Failure Syndromes metabolism, Congenital Bone Marrow Failure Syndromes pathology, Hydrazines pharmacology, Mutation, Missense, Pyrazoles pharmacology, Receptors, Thrombopoietin genetics, Receptors, Thrombopoietin metabolism, Thrombocytopenia drug therapy, Thrombocytopenia genetics, Thrombocytopenia metabolism, Thrombocytopenia pathology
Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) is a severe inherited thrombocytopenia due to loss-of-function mutations affecting the thrombopoietin (TPO) receptor, MPL. Here, we report a new homozygous MPL variant responsible for CAMT in 1 consanguineous family. The propositus and her sister presented with severe thrombocytopenia associated with mild anemia. Next-generation sequencing revealed the presence of a homozygous MPLR464G mutation resulting in a weak cell-surface expression of the receptor in platelets. In cell lines, we observed a defect in MPLR464G maturation associated with its retention in the endoplasmic reticulum. The low cell-surface expression of MPLR464G induced very limited signaling with TPO stimulation, leading to survival and reduced proliferation of cells. Overexpression of a myeloproliferative neoplasm-associated calreticulin (CALR) mutant did not rescue trafficking of MPLR464G to the cell surface and did not induce constitutive signaling. However, it unexpectedly restored a normal response to eltrombopag (ELT), but not to TPO. This effect was only partially mimicked by the purified recombinant CALR mutant protein. Finally, the endogenous CALR mutant was able to restore the megakaryocyte differentiation of patient CD34+ cells carrying MPLR464G in response to ELT., (© 2021 by The American Society of Hematology.)

Published
2021
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45. The EHA Research Roadmap: Platelet Disorders.

Author

Balduini C, Freson K, Greinacher A, Gresele P, Kühne T, Scully M, Bakchoul T, Coppo P, Dovc Drnovsek T, Godeau B, Gruel Y, Rao AK, Kremer Hovinga JA, Makris M, Matzdorff A, Mumford A, Pecci A, Raslova H, Rivera J, Roberts I, Scharf RE, Semple JW, and Van Geet C

Published
2021
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46. Induced Pluripotent Stem Cells Enable Disease Modeling and Drug Screening in Calreticulin del52 and ins5 Myeloproliferative Neoplasms.

Author

Secardin L, Gomez Limia C, da Silva-Benedito S, Lordier L, El-Khoury M, Marty C, Ianotto JC, Raslova H, Constantinescu SN, Bonamino MH, Vainchenker W, Monte-Mor B, Di Stefano A, and Plo I

Abstract

Mutations in the calreticulin ( CALR ) gene are seen in about 30% of essential thrombocythemia and primary myelofibrosis patients. To address the contribution of the human CALR mutants to the pathogenesis of myeloproliferative neoplasms (MPNs) in an endogenous context, we modeled the CALRdel52 and CALRins5 mutants by induced pluripotent stem cell (iPSC) technology using CD34 + progenitors from 4 patients. We describe here the generation of several clones of iPSC carrying heterozygous CALRdel52 or CALRins5 mutations. We showed that CALRdel52 induces a stronger increase in progenitors than CALRins5 and that both CALRdel52 and CALRins5 mutants favor an expansion of the megakaryocytic lineage. Moreover, we found that both CALRdel52 and CALRins5 mutants rendered colony forming unit-megakaryocyte (CFU-MK) independent from thrombopoietin (TPO), and promoted a mild constitutive activation level of signal transducer and activator of transcription 3 in megakaryocytes. Unexpectedly, a mild increase in the sensitivity of colony forming unit-granulocyte (CFU-G) to granulocyte-colony stimulating factor was also observed in iPSC CALRdel52 and CALRins5 compared with control iPSC. Moreover, CALRdel52-induced megakaryocytic spontaneous growth is more dependent on Janus kinase 2/phosphoinositide 3-kinase/extracellular signal-regulated kinase than TPO-mediated growth and opens a therapeutic window for treatments in CALR -mutated MPN. The iPSC models described here represent an interesting platform for testing newly developed inhibitors. Altogether, this study shows that CALR-mutated iPSC recapitulate MPN phenotypes in vitro and may be used for drug screening., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Published
2021
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47. Miniaturized 3D bone marrow tissue model to assess response to Thrombopoietin-receptor agonists in patients.

Author

Di Buduo CA, Laurent PA, Zaninetti C, Lordier L, Soprano PM, Ntai A, Barozzi S, La Spada A, Biunno I, Raslova H, Bussel JB, Kaplan DL, Balduini CL, Pecci A, and Balduini A

Subjects
Adult, Aged, Bioreactors, Blood Platelets metabolism, Cell Culture Techniques, Cells, Cultured, Female, Fibroins metabolism, Hematopoietic Stem Cells metabolism, Humans, Induced Pluripotent Stem Cells metabolism, Intercellular Signaling Peptides and Proteins genetics, Male, Megakaryocytes metabolism, Middle Aged, Miniaturization, Mutation, Myosin Heavy Chains genetics, Receptors, Thrombopoietin metabolism, Thrombocytopenia blood, Thrombocytopenia genetics, Young Adult, Benzoates pharmacology, Blood Platelets drug effects, Hematopoietic Stem Cells drug effects, Hydrazines pharmacology, Induced Pluripotent Stem Cells drug effects, Megakaryocytes drug effects, Pyrazoles pharmacology, Receptors, Thrombopoietin agonists, Stem Cell Niche, Thrombocytopenia drug therapy, Thrombopoiesis drug effects
Abstract

Thrombocytopenic disorders have been treated with the Thrombopoietin-receptor agonist Eltrombopag. Patients with the same apparent form of thrombocytopenia may respond differently to the treatment. We describe a miniaturized bone marrow tissue model that provides a screening bioreactor for personalized, pre-treatment response prediction to Eltrombopag for individual patients. Using silk fibroin, a 3D bone marrow niche was developed that reproduces platelet biogenesis. Hematopoietic progenitors were isolated from a small amount of peripheral blood of patients with mutations in ANKRD26 and MYH9 genes, who had previously received Eltrombopag. The ex vivo response was strongly correlated with the in vivo platelet response. Induced Pluripotent Stem Cells (iPSCs) from one patient with mutated MYH9 differentiated into functional megakaryocytes that responded to Eltrombopag. Combining patient-derived cells and iPSCs with the 3D bone marrow model technology allows having a reproducible system for studying drug mechanisms and for individualized, pre-treatment selection of effective therapy in Inherited Thrombocytopenias., Competing Interests: CD, PL, CZ, LL, PS, AN, SB, AL, IB, HR, DK, CB, AP, AB No competing interests declared, JB James B Bussel is consultant and participant in advisory boards for Amgen, Novartis, Dova, Rigel, UCB, Argenx, Momenta, Regeneron, (© 2021, Di Buduo et al.)

Published
2021
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49. Calreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN.

Author

Benlabiod C, Cacemiro MDC, Nédélec A, Edmond V, Muller D, Rameau P, Touchard L, Gonin P, Constantinescu SN, Raslova H, Villeval JL, Vainchenker W, Plo I, and Marty C

Subjects
Animals, Calreticulin metabolism, Disease Models, Animal, Female, Hematopoietic Stem Cells metabolism, Homozygote, Humans, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Male, Mice, Mice, Inbred C57BL, Mutagenesis, Insertional, Phenotype, Primary Myelofibrosis metabolism, Sequence Deletion, Thrombocythemia, Essential metabolism, Calreticulin genetics, Primary Myelofibrosis genetics, Thrombocythemia, Essential genetics
Abstract

Somatic mutations in the calreticulin (CALR) gene are associated with approximately 30% of essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations, including the two most frequent 52 bp deletion (del52) and 5 bp insertion (ins5), induce a frameshift to the same alternative reading frame generating new C-terminal tails. In patients, del52 and ins5 induce two phenotypically distinct myeloproliferative neoplasms (MPNs). They are equally found in ET, but del52 is more frequent in PMF. We generated heterozygous and homozygous conditional inducible knock-in (KI) mice expressing a chimeric murine CALR del52 or ins5 with the human mutated C-terminal tail to investigate their pathogenic effects on hematopoiesis. Del52 induces greater phenotypic changes than ins5 including thrombocytosis, leukocytosis, splenomegaly, bone marrow hypocellularity, megakaryocytic lineage amplification, expansion and competitive advantage of the hematopoietic stem cell compartment. Homozygosity amplifies these features, suggesting a distinct contribution of homozygous clones to human MPNs. Moreover, homozygous del52 KI mice display features of a penetrant myelofibrosis-like disorder with extramedullary hematopoiesis linked to splenomegaly, megakaryocyte hyperplasia and the presence of reticulin fibers. Overall, modeling del52 and ins5 mutations in mice successfully recapitulates the differences in phenotypes observed in patients.

Published
2020
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50. Megakaryocyte polyploidization: role in platelet production.

Author

Vainchenker W and Raslova H

Subjects
Animals, Cell Differentiation, Humans, Blood Platelets metabolism, Megakaryocytes metabolism
Abstract

Mammal megakaryocytes (MK) undergo polyploidization during their differentiation. This process leads to a marked increase in the MK size and of their cytoplasm. Contrary to division by classical mitosis, ploidization allows an economical manner to produce platelets as they arise from the fragmentation of the MK cytoplasm. The platelet production in vivo correlates to the entire MK cytoplasm mass that depends both upon the number of MKs and their size. Polyploidization occurs by several rounds of DNA replication with at the end of each round an aborted mitosis at late phase of cytokinesis. As there is also a defect in karyokinesis, MKs are giant cells with a single polylobulated nucleus with a 2 x N ploidy. However, polyploidization per se does not increase platelet production because it requires a parallel development of MK organelles such as mitochondria, granules and the demarcation membrane system. MK polyploidization is regulated by extrinsic factors, more particularly by thrombopoietin (TPO), which during a platelet stress increases first polyploidization before enhancing the MK number and by transcription factors such as RUNX1, GATA1, and FLI1 that regulate MK differentiation explaining why polyploidization and cytoplasmic maturation are intermingled. MK polyploidization is ontogenically regulated and is markedly altered in malignant myeloid disorders such as acute megakaryoblastic leukemia and myeloproliferative disorders as well as in hereditary thrombocytopenia, more particularly those involving transcription factors or signaling pathways. In addition, MKs arising from progenitors in vitro have a much lower ploidy in vitro than in vivo leading to a low yield of platelet production in vitro . Thus, it is tempting to find approaches to increase MK polyploidization in vitro . However, these approaches require molecules that are able to simultaneously increase MK polyploidization and to induce terminal differentiation. Here, we will focus on the regulation by extrinsic and intrinsic factors of MK polyploidization during development and pathological conditions.

Published
2020
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