Transgenic mouse models provide the possibility to study cancer progression in vivo in a controlled, experimentally manipulable manner. The Myc oncogene is deregulated in a wide range of human cancers, and its activity is often associated with highly aggressive tumor behavior. Myc is a transcription factor that regulates the expression of several thousand genes both directly and through its effects on chromatin structure. Further, Myc is a key factor in induced pluripotency whereby fully differentiated cells can be converted to a pluripotent state by provision of four reprogramming factors (Sox2, Nanog, Oct4, and Myc). Although expression of Myc is required at various stages for correct development of normal hematopoietic lineages, this occurs under strict regulatory constraints. Sustained inappropriate over-expression of Myc leads, in many cases, to tumorigenesis. We have previously studied the ability of Myc to induce tumors in liver, osteosarcoma, and T-cell lymphoma transgenic mouse models. Here, we will focus on analysis of Myc-induced lymphomas, synergistically with our study of human lymphoid and myeloid malignancy. Our mouse model will enable us to analyze induction of self-renewal programs leading to tumor formation, in a controlled context with a specific mechanism of action (Myc over-expression). Using this system, we can also cause tumors to regress and then relapse, permitting analysis of the latter phenomenon and how it relates to cell states. Further, by manipulating genes such as P53, PI 6, Bim inactivation we will perturb processes of apoptosis and senescence to determine their effects on tumor onset and regression.
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