In this proposal we aim to identify the plasma membrane (PM) and associated proteins involved specifically in B-cells of patients with chronic lymphocytic leukemia (CLL) and not in the healthy B-cells. The alterations occurring at the PM at the CLL cells will be further explored on molecular and functional level. To gain insights into comprehensive membrane protein changes during CLL, we plan to perform a comparative proteomic analysis using two proteomic methods – quantitative proteomics of plasma membrane and immunoprecipitation coupled to mass-spectrometry (IP/MS) of selected membrane proteins related to the WNT pathway (Ror1, Celsr1, Vangl2 and Frizzleds). Plasma membranes of B-cells from healthy/non-progressive/progressive patients, or from cells stimulated with extracellular stimuli (with Wnt, chemokine or both) will be analyzed. We presume that by using proteomic approach we will be able to identify some receptor and effector molecule bridging Wnt signaling pathway (canonical and Non-cononical) with CLL disease progression. . We believe that elucidating the profile of extracellular integral membrane proteins on live cells will be vital for uncovering diagnostic disease biomarkers, therapeutic agents and drug receptor candidates.