Murine Leukemia/Lymphoma Modeling
Chronic lymphocytic leukemia (CLL) is a conceptually very special disease in that its tumor cells on their own are almost completely incompetent with regards to self-renewal and clonal maintenance. In fact CLL derives only a minor part of its proliferative and survival cues from mutations and instead relies heavily on immune and stromal interactions in specific microenvironments. Modeling of these complex microenvironmental interactions with T and NK cell components, myeloid and mesenchymal stromal components quickly reaches technical limitations in vitro, although such models are also a focus of this workgroup. It is, however, clear that an optimized model in an experimental organism is necessary to mimic such complex microenvironments and our group has adopted genetically modified mice that develop a murine CLL-like disease to answer a number of questions. Using the TCL-transgenic CLL model we have established methods for genetic modifications of tumor cells and for genetic and non-genetic modifications of microenvironmental components, separately, using crossing and transplantation strategies. All these models are paralleled by investigations in human ex vivo model systems to verify the relevance of the murine findings to human CLL. Our main goal is to identify the genetic and cellular basis of the regulation of cell proliferation and death, as well as of treatment resistance in CLL. Such information will define better targets for therapeutic approaches in CLL. With this strategy we have previously defined components of the B cell receptor signaling pathway as potential treatment targets and this group of targets is currently in intensive clinical development. In addition, we have defined essential genes for microenvironmental support that also could be exploited therapeutically.
Lutzny G, Kocher T, Schmidt-Supprian M, Rudelius M, Klein-Hitpass L, Finch AJ, et al. Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer cell 2013;23:77-92. IF: 23.8
Weiss L, Melchardt T, Neureiter D, Kemmerling R, Moshir S, Pleyer L, et al. Complete remission of Waldenstrom macroglobulinemia with azacitidine and rituximab. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011;29:e696-8. IF: 18.0
Labi V, Erlacher M, Krumschnabel G, Manzl C, Tzankov A, Pinon J, et al. Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev 2010;24:1602-7. IF: 12.6
Alexander Egle, MD
IIIrd Medical Department
University Clinics Salzburg
Paracelsus Medical Private University
in vivo modeling of leukemia
A major focus of the lab is on cellular rheostats that integrate microenvironmental signals in order to direct the functional state of CLL. Understanding such rheostats will not only lead to potential targeting of such cellular components, but also allow to use their signals as flags in order to predict optimal combination treatment attacking several upstream targets with synergistic intention. These avenues are currently pursued in a number of national and international grants.