Two decades of cancer genetics: from specificity to pleiotropic networks

Modeling cancer in mice has reached an even greater relevance in the field of hematological malignancies, due to the already advanced characterization of the molecular basis of many hematological disorders. These mouse models have often allowed us to achieve insight into the pathogenesis of the human disease as well as to test novel therapeutic modalities in preclinical studies. However, one of the most rewarding cultural shifts triggered by these modeling efforts stems from what was originally perceived as background noise or modeling inaccuracy. Manipulation of the involved genes often triggered cancer susceptibility in cell types other than the hematopoietic lineages. This prompted us to challenge a fundamental misconception in cancer genetics that the approximately 200 genes directly involved in chromosomal translocations associated with hematopoietic malignancies are specifically and functionally restricted to leukemia/lymphoma pathogenesis only. The genetics underlying the pathogenesis of leukemia and lymphoma have historically been regarded as distinct from those underlying the pathogenesis of solid tumors because hematopoietic malignancies are often associated with characteristic chromosomal translocations that are leukemia- or lymphoma-specific. In this paper, we discuss how leukemia/lymphoma genes indeed participate in fundamental proto-oncogenic and growth-suppressive networks and may play a wider role in cancer pathogenesis. We focus on paradigmatic examples such as c-myc and PML, as well as on more recent findings from our laboratory concerning the role of NPM in tumorigenesis.