Grant: Master's Award: Canada Graduate Scholarships

Tumor Necrosis Factor Receptors (TNFRs) become constitutively turned on in many instances of B cell cancers. In turn, these receptors recruit TNF Receptor Associated Factor Proteins (TRAFs) to activate Nuclear Factor­-kB (NF­kB), a master of transcription that promotes survival and proliferation of B cells. One member of this family, TRAF1 forms a heterotrimer with TRAF2 to facilitate the recruitment of Cellular Inhibitor of Apoptosis Proteins (cIAPs). cIAPs, in turn, are critical for the formation of a complex signaling platform that culminates in the activation of NF­kB. TRAF1 is of specific interest, as it is over­ expressed in 48% of B cell malignancies. Uniquely, TRAF1 is the only member of its family that can be phosphorylated by Protein Kinase 1 (PKN1) at the serine at position 146 (S146). We hypothesize that pTRAF1 can predict whether Chronic Lymphocytic Leukemia (CLL) patients would be sensitive to PKN1 inhibitors, which can later be extended to Multiple Myeloma (MM) patients (have up­regulated TRAF1). We also hypothesize that pharmacological or genetic reduction of PKN1 levels in MM patient samples and cell lines will reduce TRAF1 phosphorylation and its protein levels, and thereby lower downstream survival signaling and increase cell death. There is currently no method to confirm the direct phosphorylation of TRAF1, due to the lack of a phospho­-specific antibody. Our first aim is to validate the phospho­-S146 specific (pTRAF1) monoclonal antibodies that have been developed for us by Abcam, which can later serve as a biomarker for CLL and MM. Our second aim is to determine whether targeting PKN1 leads to reduced TRAF1 expression and downstream signaling in MM, allowing us to investigate the role of PKN1 as a new potential target in MM.