Mechanisms of Insertional Transformation

Group members: Olga Kustikova, Teng Cheong Ha, Maike Stahlhut, Christopher Baum

Contributing Principal Investigators: Ute Modlich, Zhixiong Li, Axel Schambach, Johann Meyer

The untargeted integration of replication-deficient retroviral vectors in hematopoietic stem cells may lead to the upregulation or downregulation of genes that play a critical role in hematopoiesis. Together with our colleague B. Fehse (Hamburg, Germany) we have embarked to explore the potential of using retroviral insertional mutagenesis as a tool to identify novel genes that improve the competitive fitness of normal and malignant hematopoietic stem cells. One aim of this research is to identify novel molecular approaches to trigger stem cell proliferation and hematopoietic regeneration without interfering with differentiation. Another aim is the discovery of important pathways that trigger induction and progression of malignant proliferation of hematopoietic cells, i.e. leukemia. Finally, we develop preclinical model systems that allow a sensitive detection of insertional clonal imbalance in gene-modified hematopoiesis, thus promoting the rational development and experimental validation of safe gene vectors.

Selected own references:

Maetzig T, Brugman MH, Bartels S, Heinz N, Kustikova OS, Modlich U, Li Z, Galla M, Schiedlmeier B, Schambach A, Baum C. Polyclonal fluctuation of lentiviral vector-transduced and expanded murine hematopoietic stem cells. Blood 2011; 117:3053-3064.

Kustikova OS, Schiedlmeier B, Brugman MH, Stahlhut M, Bartels S, Li Z, Baum C. Cell-intrinsic and vector-related properties cooperate to determine the incidence and consequences of insertional mutagenesis. Molecular Therapy 2009; 17:1537-1547

Kustikova O, Geiger H, Li Z, Brugman MH, Chambers SM, Shaw CA, Pike-Overzet K, de Ridder D, Staal FJT, Keudell G, Cornils K, Nattamai KJ, Modlich U, Wagemaker G, Goodell MA, Fehse B, Baum C. Retroviral vector insertion sites associated with dominant hematopoietic clones mark “stemness” pathways. Blood 2007; 109:1897-1907

Baum C, Kustikova O, Modlich U, Li Z, Fehse F. Mutagenesis and oncogenesis by chromosomal insertion of transgene vectors. Human Gene Therapy 2006; 17:253-263

Kustikova O, Fehse B, Modlich U, Düllmann J, Kamino K, von Neuhoff N, Yang M, Schlegelberger B, Li Z*, Baum C. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking. Science 2005; 308: 1171-1174. 

go to top