AG Leukemogenesis and Molecular Therapy
Prof. Zhixiong Li, MD
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
OE 6860
Building K04, Level H0, Room 1180
Medizinische Hochschule Hannover
Carl-Neuberg-Str. 1
30625 Hannover
Tel: +49-511-532 9383
Fax: +49-511-532-18586
E-Mail: li.zhixiong@mh-hannover.de
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation
Hannover Medical School
Carl-Neuberg-Str. 1
30625 Hannover
Germany
Phone: 0049 511-532 9383
Fax: 0049 511-532 18586
E-Mail: li.zhixiong@mh-hannover.de
We are seeking MD or PhD students for our ongoing projects. Doctoral students will get a stipend (usually 1200€/month) from our projects, limited first for one year (with the opportunity to prolong). If interested, please contact Prof. Li (see above).
Our group is interested in understanding how receptor protein tyrosine kinases (PTKs) contribute to development of leukemia and systemic mastocytosis. Receptor PTKs are often deregulated in human cancers and may be important for self-renewal of cancer stem cells. Thus, receptor PTKs represent attractive targets for selective molecular therapy. Our work has focused in part on the neurotrophin receptors and FLT3 signaling pathways. Neurotrophins (NTs, e.g. BDNF=brain-derived neurotrophic factor) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor PTKs (TRKA, TRKB, TRKC) are high affinity NT-receptors that are expressed in a variety of human tissues. However, we and others have recently obtained evidence for a potential involvement of this receptor system in leukemia and mast cell disorders. To study the TRK pathway and other important cellular networks, we have currently established mouse models for leukemogenesis through altered TRK signaling and performed molecular analysis in primary samples from patients with acute leukemia. Our data suggested that TRKs and their downstream signaling partners (e.g. mTOR) might serve as attractive therapeutic targets in acute leukemias and mastocytosis. Prof. Li is a member of the EMBRN (European Mast Cell and Basophil Research Network) and the ECNM (The European Competence Network on Mastocytosis). Moreover, Prof. Li has long-term experiences in the development of retroviral vector systems for gene transfer into hematopoietic stem cells (HSCs) and T cells, and in preclinical gene therapy trials.
Our research has been funded by
- Deutsche Forschungsgemeinschaft (DFG),
- Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS),
- Alfred & Angelika Gutermuth-Stiftung
Li ZX, Schade UM, Fehse B, Stockschläder M, Uhde A, Koch S, Goller B, Rüger R, Fehse N, Zander AR. High-efficient retroviral vector-mediated gene transfer into human T lymphocytes. Adv Exp Med Biol 1998; 451:375-378
Li Z*, Yin S, Xie S, Ma L, Nie D, Xsu L. (*corresponding author) Treatment of severe aplastic anemia using high-dose Cyclophosphamide alone in China. Haematologica 2000;85(E-letters):06 (http://www.haematologica.it/e-letters)
Li Z, Fehse B, Schieldmeier B, Düllmann J, Frank O, Zander AR, Ostertag W, Baum C. Persisting multilineage transgene expression in the clonal progeny of a hematopoietic stem cell. Leukemia 2002;16:1655-63
Li Z, Düllmann J, Schiedlmeier B, Schmidt M, von Kalle C, Meyer J, Forster M, Stocking C, Ostertag W, Wahlers A, Frank O, Kuehlcke K, Eckert HG, Fehse B, Baum C. Murine leukemia induced by retroviral gene marking. Science 2002; 296:497
Li Z, Schwieger M, Lange C, Kraunus J, Sun H, van den Akker E, Modlich U, Serinsöz E, Will E, von Laer D, Stocking C, Fehse B, Schiedlmeier B, Baum C. Predictable and efficient retroviral gene transfer into murine bone marrow repopulating cells using a defined vector dose. Experimental Hematology 2003; 31:1206-1214
Schiedlmeier B, Klump H, Will E, Arman-Kalcek G, Li Z, Wang Z, Friel J, Baum C, Ostertag W. High level ectopic HOXB4 expression confers a profound in vivo competitive growth advantage to human cord blood CD34+ cells, but impairs lymphomyeloid differentiation. Blood 2003;101:1759-68.
Baum C, Duellmann J, Li Z, Fehse B, Meyer J, Williams DA, C von Kalle. Side effects of retroviral gene transfer into hematopoietic stem cells. Blood 2003; 101:2099-2113.
Beutel G, Meyer J, Ma L, Yin S, Eder M, von Neuhoff N, Wilkens L, Wie J, Hertenstein B, Heil G, Schlegelberger B, Ganser A, Li Z*, Baum C. (*corresponding author) Expression of the p75 neurotrophin receptor in acute leukaemia. British Journal of Haematology 2005; 131:67–70
Kustikova O, Fehse B, Modlich U, Yang M, Düllmann J, Kamino K, von Neuhoff N, Schlegelberger B, Li Z*, Baum C*. (*co-corresponding author) Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 2005; 308:1171-1174
Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K, Neumann T, Yang M, Wahlers A, Fehse B, Schlegelberger B, Reuther GW, Ganser A, Baum C, Li Z. Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, DTrkA. Leukemia 2007; 21:2171-2180
Li Z*, Beutel G, Rhein M, Meyer J, Koenecke C, Neumann T, Yang M, Krauter J, von Neuhoff N, Heuser M, Diedrich H, Göhring G, Wilkens L, Schlegelberger B, Ganser A, Baum C*. (*co-corresponding author) Neurotrophin receptors and ligands promote leukemogenesis. Blood 2009;113(9):2028-37.
Rhein M, Schwarzer S, Yang M, Kaever V, Brugman M, Meyer J, Ganser A, Baum C, Li Z. Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models Annals of Hematology 2011;90:283-292
Skokowa J, Klimiankou M, Klimenkova O, Lan D, Gupta K, Hussein K, Carrizosa E, Kusnetsova I, Li Z, Sustmann C, Ganser A, Zeidler C, Kreipe HH, Burkhardt J, Grosschedl R, Welte K. Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nat Med. 2012 Sep 23;18(10):1550-9.
Yang M, Büsche G, Ganser A, Li Z. Morphology and quantitative composition of hematopoietic cells in murine bone marrow and spleen of healthy subjects. Annals of Hematology 2013; 92(5):587-94.
Yang M, Huang K, Büsche G, Ganser A, Li Z. Activation of TRKB receptor in murine hematopoietic stem/progenitor cells induced mastocytosis. Blood. 2014;124:1196-7.
Stahlhut M, Schwarzer A, Eder M, Yang M, Li Z, Morgan M, Schambach A, Kustikova OS. Lentiviral vector system for coordinated constitutive and drug controlled tetracycline-regulated gene co-expression. Biomaterials. 2015 Sep;63:189-201.
Huang K, Yang M, Pan Z, Heidel FH, Scherr M, Eder M, Fischer T, Büsche G, Welte K, von Neuhoff N, Ganser A, Li Z. Leukemogenic potency of the novel FLT3-N676K mutant. Annals of Hematology 2016 95(5):783-91.
Yang M, Pan Z, Huang K, Büsche G, Feuerhake F, Chaturvedi A, Nie D, Heuser M, Thol F, von Neuhoff N, Ganser A, Li Z. Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy. Oncotarget 2017; 8:73871-73883.
Pan Z, Yang M, Huang K, Büsche G, Glage S, Ganser A, Li Z. Flow cytometric characterization of acute leukemia reveals a distinctive “blast gate” of murine T-lymphoblastic leukemia/lymphoma. Oncotarget 2018; 9:2320-2328.
Pan Z, Yang M, Huang K, Büsche G, Göhring G, Scherr M, Gaestel M, Eder M, Skokowa J, Zhou J, Welte K, Liu L, Ganser A, Li Z. Synergy between FLT3-ITD and p53 haploinsufficiency or loss in the development of acute myeloid leukemia. Blood 2018, Abstract #771 (oral presentation, ASH meeting 2018).