Possible pitfalls investigating cell death responses in genetically engineered mouse models and derived cell lines

Genetically engineered mouse models are frequently used to identify pathophysiological consequences of deregulated cell death. Targeting pro-apoptotic or anti-apoptotic proteins of the extrinsic or intrinsic apoptotic signalling cascade is state of the art since more than two decades. Such animal models have been increasingly made use of over the past years to study loss- or gain-of-function consequences of one or more components of the molecular machinery leading to cell death. These studies have helped to separate redundant from non-redundant functions of apoptosis-related proteins in normal physiology and sometimes unravelled unexpected phenotypes. However, correct interpretation of data derived from knockout mice or derived cells and cell lines is often flawed by the comparison of cells originating from different inbred or mixed genetic backgrounds. Here we want to highlight some basic problems associated with genetic background-based modulation of cell death sensitivity and describe some methods that we use to investigate cell death responses in hematopoietic and non-hematopoietic cells. Thereby, we show that hematopoietic cells derived from wild type mice on a C57BL/6:129/SvJ recombinant mixed genetic background are significantly more resistant to spontaneous cell death or DNA-damage induced apoptosis in vitro than cells derived from inbred C57BL/6 mice. Furthermore, we show as an example that C57BL/6 mice are more susceptible to γ-irradiation induced cell death after whole body irradiation in vivo and subsequent T cell lymphomagenesis.