T cell receptor dependent transformation of mature memory phenotype T cells

A fundamental goal in cancer research is identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth as this has the potential to reveal features that can be exploited therapeutically. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies but are unlikely to underlie initiation of mature lymphoid neoplasms, the cellular origin of which remains unclear. Here, we used a conditional Snf5 model to investigate the origin of peripheral T cell lymphomas. We find that the cell of origin is a mature CD44hiCD122lo CD8 T cell that resembles a subset of memory cells, a population with capacities for self-renewal and robust expansion - features shared with stem cells. We elucidate mechanism by showing that Snf5 loss leads to activation of a Myc network and stem cell transcriptional program. Finally, we demonstrate that lymphomagenesis depends upon TCR signaling, establishing a new paradigm for lymphomagenesis. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells is associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers. Stable mouse Snf5-deficient T cell lymphoma cell lines were established. CD44hi and CD44lo subpopulations were purified and used to evaluate gene expression pattern in these two subpopulations. RNA was isolated from each of these samples and used for gene expression profiling on Affymetrix 430A arrays.