Changes in intracellular protein levels, subcellular localization, or activation state are considered to be reflective of a cell's capabilities or functions. Some of these events are relatively transitory - such as some phosphorylation of proteins in cell signaling cascades. Some of the relevant cell populations are so rare as to make their isolation for standard biochemical analysis nearly impossible. Remodeling of such cell signaling mechanisms drives tumor proliferation and suppresses apoptosis, contributing to tumor survival despite intense therapy regimens. Therefore, to understand how signaling networks are remodeled in hematological tumors there is a need to measure complex populations of immune system cells and phenotype them not only for their cell lineage status but also for their relative activation state. The central hypothesis of these studies is that patients whose tumors share similar mechanisms of proliferative and anti-apoptotic signaling will respond similarly to a defined tumor cell killing regimen. Underlying this idea is the additional hypothesis that heritable differences among tumors will detectably modify tumor cell signaling networks. A long range goal in this project is to develop a predictive model of FL clinical outcome based on molecular mechanisms of signaling detected in heterogeneous tumor cell populations. In addressing this goal, we will a) construct a signaling taxonomy of FL, b) delineate remodeled signaling mechanisms in FL tumor cells, and c) correlate profiles of signaling in lymphoma with both heritable changes in tumors and clinical measures of disease aggressiveness. We will also test the hypothesis that cell by cell enumeration of signaling mechanisms will reveal the nature of the tumor - host interaction and distinguish tumor cell subsets whose presence and signaling state correlate with disease outcome.