A Bioinformatics Approach Revealed a Differential Expression of RKIP-Related Genes in Pre-Multiple Myeloma and Multiple Myeloma: Clinical Implications

Introduction: 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 and a heterogeneous disease. The metastatic suppressor/anti-resistance factor, Raf-1 kinase inhibitor protein (RKIP), is poorly expressed in the majority of cancers. In contrast, inactive phosphorylated RKIP is overexpressed in MM and assisting in cell proliferation and resistance. Active RKIP inhibits the RAF/MEK/ERK1/2 and NF-κB pathways.

Rationale: A molecular identification of stage-specific pre-MM and MM biomarkers will support a more precise diagnosis/prognosis, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets.

Objective: To identify RKIP-related gene products in pre-MM and MM as novel biomarkers and therapeutic targets.

Hypothesis: We hypothesized that there would be differential molecular signatures between the pre-MM and MM disease-related to RKIP-regulated genes.

Methodology: We examined transcriptomic datasets on Oncomine platform (Life Technologies) for pre-MM and MM.

Results: Several gene products were found to be commonly overexpressed (e.g., RKIP, Bcl-2 and DR5); and underexpressed (e.g., Bcl-6 and TNFR-II) in both pre-MM and MM, suggesting a plausible distinctive general molecular signature of the disease. Importantly, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF -α and underexpression of YY1; versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF -α.

Conclusion and Future Directions: The findings suggested differential molecular signatures between pre-MM and MM. We are currently analyzing the relationship between RKIP and both overexpressed and underexpressed gene products to identify molecular pathways with cross-talks for the regulation of RKIP.

Clinical Implication: The proposed findings might lead to a more precise diagnosis/prognosis of MM and its disease stages, and can identify novel molecular therapeutic targets for pre-MM and MM.