Overexpression of Raf Kinase Inhibitor Protein (RKIP) in Multiple Myeloma and Its Molecular Signature

Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS) that can evolve to asymptomatic pre-MM and later to symptomatic MM. MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) inhibits the Raf/MEK/ERK1/2 and NF-κB pathways and sensitizes resistant tumors to drug-induced apoptosis. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our prior findings demonstrated that RKIP is overexpressed (primarily in its inactive phosphorylated form) in MM cell lines and patients-derived tumor tissues (Baritaki et. al, FIDT 2:1-13, 2011). We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the expression of RKIP and several-associated gene products in both pre-MM and MM. Several gene products were found to be overexpressed such as RKIP, Bcl-2, and DR5 and underexpressed such as Bcl-6 and TNFR2 in both pre-MM and MM. A differentially expressed pro-apoptotic genes were observed in pre-MM versus expression of anti-apoptotic genes in MM. Based on these analyses on mRNA levels and on protein levels in published studies of the above differentially expressed genes, we have found a molecular signature each for pre-MM and MM. Once the molecular signatures are validated experimentally, they will be useful for a more precise diagnosis/prognosis of the disease stages and will also identify novel molecular therapeutic targets.