Multiple Myeloma and Bone Marrow Mesenchymal Stem Cells` Crosstalk: Effect on Translation Initiation

Multiple myeloma (MM) malignant plasma cells reside in the bone marrow (BM) and convert it into a specialized pre-neoplastic niche that promotes the proliferation and survival of the cancer cells. BM resident mesenchymal stem cells (BM-MSCs) are altered in MM and in vitro studies indicate their transformation by MM proximity is within hours. The response time frame suggests that protein translation may be implicated. Thus, we assembled a co-culture model of MM cell lines with MSCs from normal donors (ND) and MM patients to test our hypothesis. MM cell lines (U266, ARP1) and BM-MSCs (ND, MM) were harvested separately after 3 days of co-culture and assayed for proliferation, death, levels of major translation initiation factors (eIF4E, eIF4GI), their targets, and regulators.

Significant changes were observed: ND and MM BM-MSCs co-cultured with MM cell lines displayed elevated proliferation, death, and expression/activity of eIF4E/eIF4GI; MM cell lines co-cultured with MM-MSCs also displayed higher proliferation, death and eIF4E/eIF4GI; in contrast, MM cell lines co-cultured with ND-MSCs did not display elevated proliferation, only death and had no changes in eIF4GI levels/activity and un-uniform levels of eIF4E. We also determined that the MM induced changes in ND-MSCs` eIF4E/eIF4GI are reversible. Lastly, we showed that MM cell lines proximity to ND-MSCs caused elevated migration of MSCs. We depict a flowchart of our observations.

Our study demonstrates that there is direct dialogue between the MM and BM-MSCs populations that includes translation initiation manipulation and critically affects cell fate. Future research should be aimed at identifying therapeutic targets that may be used to minimize the collateral damage to the cancer microenvironment and limit its recruitment into the malignant process.