Multiple Myeloma Cells Reprogram Bone Marrow Mesenchymal Stem Cells` Translation Initiation thereby Promoting their Migration

Background and objectives: Previously, we showed co-modulation of translation initiation (TI) in BM-MSCs from normal donors (ND) co-cultured with MM cells. Here, we characterized the time line of MSCs conditioning by multiple myeloma (MM) cells, the persistence of this effect, and the consequences on cell phenotype.

Methods: ND-MSCs were co-cultured with MM cell lines (U266, ARP1) (MMcond-MSCs)(1-3 days), counted and assayed for death (trypan blue), viability (WST1), migration (scratch assay, inhibitors), expression of TI factors, regulators and targets (immunoblotting). Involvement of MAPKs in MSCs conditioning and altered migration was tested (immunoblotting, inhibitors). MMcond-MSCs were re-cultured alone (1-7 days) and assayed for TI. qPCR of extracted RNA was tested for microRNAs levels.

Results: MMcond-MSCs increased TI (↑150-200%, p<0.05) and proliferation (↑130%, p<0.01) is evident after 2 days of co-culture and persists on the 3^rd day. The regulators are increased after 1 day and persist on the 2^nd day (↑>220%, p<0.05), whereas the targets peak on the 3^rd day (↑>250%; p<0.05). MAPKs are activated within 1.5h of co-culture and responsible for MMcond-MSCs TI status (↑~>200%, p<0.05) and elevated migration (16h, ↑~>400%, p<0.05). The BM-MSCs conditioning by MM cells is reversible after only 1 day of MMcond-MSCs culture alone. Decreased expression of MIR199 and MIR125a (↑~<140%, p<0.05) in MMcond-MSCs supports elevated migration.

Discussion: Time and proximity dependent conditioning of ND-MSCs underscores the dynamic co-evolution of MM and BM-niche. MAPK/TI induced MMcond-MSCs migration may contribute to disease progression and additional studies are warranted to establish its potential as an effective therapeutic target.