Oncoprotein 18 (Op18) : A Differentially Expressed Gene Is a Novel Therapeutic Target in Multiple Myeloma

Stathmin(Op18) is a ubiquitous cytosolic 18Kda protein regulating microtubule (MT) dynamics via binding and stabilizing activities. The activity of Op18 is down regulated during cell cycle by phosphorylation at four Ser residues. The phospho-Op18 is unable to bind to tubulin allowing the progression of the cell cycle. Two additional Op18-binding proteins, KIS prevents Op18 dephosphorylation and activation while iASPP (inhibitor of apoptosis stimulatory protein phosphatase) binds to WT-p53 and inhibits p53-related apoptosis. We have identidfied Op18 as a differentially expressed gene by suppression subtractive hybridization in myeloma. We have also confirmed differential expression of KIS in myeloma cells compared to normal plasma cells. Overexpression of Op18 was confirmed at both RNA and at protein level by RT –PCR and Western blotting in human myeloma cell lines as well as primary samples compared to normal plasma cells and normal human fibroblasts. In contrast, none of the tonsillar CD138+ plasma cells and normal bone marrow mononuclear cells showed Op18 overexpression. To establish the role of Op18 overexpression in MM cell transformation, the human MM cell lines were treated with antisense Op18 oligodeoxynucleotides (ODN). The growth rate of the ODN treated human myeloma cells was significantly reduced compared to the control cells along with cell cycle arrest in G2/M phase and increase in apoptosis as measured by immunohistochemical staining. Additionally, we have silenced Op18 by transfecting Op18-specific siRNA in MM cells and observed that KIS is translocated to cytoplasm, from nucleus as well as MM cells are arrested in G2/M. Importantly, Op18 silencing increased sensitivity of MM cells to microtubule drugs suggesting possible combination approach for therapeutic application. Its role in networking cellular signal transduction pathways in myeloma is under investigation. Recent publication identifying Op18 as one of the 15 most relevant genes determining outcome in myeloma (Avet-loiseau et al, JCO 2008) adds to the validity of Op18 as a molecule playing important role in myeloma cell growth and survival and warrant investigation as a novel therapeutic target.