פרופ' דרורית נוימן

Erythropoietin and Its Receptor in Health and Disease – Basic and Clinical Aspects

Our research is focused on erythropoietin (EPO), the major hormone that regulates erythropoiesis, operating via activation of its cell surface receptor (EPO-R) on erythroid progenitor cells. Our choice to work on this EPO/EPO-R system was initiated to employ it as a model for understanding basic mechanisms of hormone/receptor function and regulation. Through this research we made a novel, original discovery, together with Prof. Mittelman from the Sourasky Medical Center, suggesting that EPO may actually act as a pleiotropic hormone with anti-neoplastic, immunomodulatory activities.

Our research is thus focused on both the basic mechanisms of hormone/receptor interaction, as well as the function of this hormone as an immunomodulator. The studies are based on a variety of in-vitro and murine experimental models, and include also an avenue of elucidating the relevance and possible clinical application of the results.

Publications

Katz O., M. Stuible, N. Golishevski, L.Lifshitz, M. L. Tremblay, M. Gassmann, M. Mittelman and D. Neumann. Erythropoietin treatment leads to reduced blood glucose levels and body mass: Insights from murine models. J. Endocrinology, 205:87-95 (2010)

Liron T., T. Nahari, M. C. Souroujon and D. Neumann. Insertion of an NPVY sequence into the cytosolic domain of erythropoietin receptor selectively affects erythropoietin mediated signaling and function. Biochem. J. 427:305-312 (2010) *Selected by Faculty of 1000: http://www.f1000biology.com/article/id/3771958/evaluation

Bishara A., A. Rudi, M. Aknin, D. Neumann, N. Ben-Califa, Y. Kashman. Salarins D–J. Seven new nitrogenous macrolides from the madagascar sponge Fascaplysinopsis sp. Tetrahedron 66, 4339–4345 (2010)

Lifshitz L., G. Tabak, M. Gassmann, M. Mittelman, and D. Neumann. Macrophages as novel target cells for erythropoietin. Haematologica 95:1823-1831, (2010)

Ben-Califa N., A. Bishara, Y. Kashman and D. Neumann. Salarin C, a member of the salarin superfamily of marine compounds, is a potent inducer of apoptosis. Invest. New Drugs 30:98-104 (2012)

Yosha L., O. Ravid, N. Ben-Califa, and D. Neumann. Cytosolic lysine residues enhance anterograde transport and activation of the erythropoietin receptor. Biochem. J. 435:509-518 (2011)

Inbar D., M. Cohen-Armon and D. Neumann. Erythropoietin driven signaling and cell migration mediated by polyADP-ribosylation, Brit. J. Cancer 107: 1317-1326 (2012)

Oster H. S., S. Prutchi-Sagiv, O. Halutz, E. Shabtai, M. Hoffman, D. Neumann, M. Mittelman.  Erythropoietin treatment is associated with an augmented immune response to the influenza vaccine in hematologic patients. Exp. Hematol. 41:167-71 (2013)

Bento C., M Percy, H. Cario*, B. Gardie, T. M. Magalhães, R. van Wijk, S. Perrotta, D. R. Fulvi, H. Almeida, C. Rossi, F. Girodon, M. Åström, D. Neumann, S. Schnittger, B. Landin, M. Minkov, M. L. Randi, S. Rives, L. Ribeiro, S. Hermouet, M. F. McMullin*, on behalf of ECE-Consortium§ Genetic basis of Congenital Erythrocytosis: mutation update and online databases. Hum Mut, 35:15–26 (2014)

Reinbothe S., A.M. Larsson, M. Vaapil, C. Wigerup, J. Sun, A. Jögi, D. Neumann, L. Rönnstrand, S. Påhlman EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation Biochem. Biophys. Res. Com. 445: 163–169 (2014)

Ohana Haim Y., N. Deshet Unger, M. C. Souroujon, M. Mittelman and D. Neumann Resistance of LPS-activated bone marrow derived macrophages to apoptosis mediated by dexamethasone Sci. Rep. 4: 4323 (2014)

Gross M., N. Ben-Califa, M. F. McMullin, M. J. Percy, C. Bento, H. Cario, M. Minkov and D. Neumann. Polycythemia-inducing mutations in the erythropoietin receptor (EPOR): Mechanism and function as elucidated by epidermal growth factor receptor (EGFR) – EPOR chimeras. Br. J. Haematol. 165:519-28 (2014)

Maxwell P., F. Melendez-Rodríguez, K. B Matchet, J. Aragones, N. Ben-Califa, H. Jaekel, L. Hengst, H. Lindner, A. Bernardini, U. Brockmeier, J. Fandrey, F. Grunert, H. Oster, M. Mittelman, M. El-Tanani, M. Thiersch, E. M. Schneider Gasser, M. Gassmann, D. Dangoor, R. J. Cuthbert, A. Irvine, A. Jordan, T. Lappin, J. Thompson and D. Neumann. Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation. Br. J. Haematology 168:429-42 (2015). *The work represents efforts of European consortium EpoCan, FP7 call, coordinated by Prof D. Neumann.

Hiram-Bab S., T. Liron, N. Deshet-Unger, M. Mittelman, M. Gassmann, M. Rauner, K. Franke, B. Wielockx, D. Neumann and Y.l Gabet. Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J. 29(5):1890-900, (2015) Commentary on manuscript: Nat Rev Endocrinol. 11:2643-2644.2015

Rauner M, K. Franke, M. Murray RP Singh, S. Hiram- Bab, U. Platzbecker, M. Gassmann, M. Socolovsky, D. Neumann, Y. Gabet, T. Chavakis, LC Hofbauer, B. Wielockx. Increased EPO levels are associated with bone loss in mice lacking phd2 in epo-producing cells. J Bone Miner Res. 2016 in press

Erythropoietin treatment in murine multiple myeloma: immune gain and bone loss Deshet-Unger N., S. Hiram-Bab, Y. Haim-Ohana, M. Mittelman, Y. Gabet, D. Neumann. Sci Rep. in press

Chapters & Reviews

Mittelman M., H.  S. Oster, M. Hoffman and D. Neumann. The lower risk MDS Patient a risk of rapid progression. Leuk. Res 34:1551-555 (2010)

Oster H.  S., D. Neumann, M. Hoffman and M. Mittelman. Erythropoietin: the swinging pendulum. Leuk. Res. 36:939-44 (2012)

Ohana Y., Liron T., Prutchi-Sagiv, S., Mittelman M. Souroujon M.C. and D. Neumann. Erythropoietin. Second edition, Handbook of Biologically Active Peptides (Abba J. Kastin, ed.), Elsevier, San Diego, pp. 1619-1626 (2013)

Hiram-Bab S, Neumann D, Gabet Y. Erythropoietin in bone - Controversies and consensus. Cytokine. 2016 in press