Proviral Integration Site for Moloney Murine Leukemia Virus 2 Suppresses Fibronectin 1 to Drive Adhesion Loss and Epithelial-Mesenchymal Transition in Multiple Myeloma

Tumor-associated macrophages (TAMs) critically shape the multiple myeloma (MM) microenvironment, yet the molecular programs linking immune signaling to MM dissemination remain unclear. Here, we identify a TAM-derived IL6-STAT3-PIM2-cMyc-FN1 axis that governs cell adhesion and epithelial-mesenchymal transition (EMT) in MM. Proviral Integration Site for Moloney murine leukemia virus 2 (PIM2) acts as a central effector by transcriptionally suppressing fibronectin 1 (FN1) via stabilization of c-Myc, thereby reducing MM-stromal adhesion and promoting migratory capacity. IL6-family cytokines secreted by M2-like TAMs activate STAT3 to induce PIM2 expression, forming a feed-forward loop that reinforces the EMT-like phenotype. Functional assays confirm that PIM2 knockdown restores FN1, increases adhesion, and impairs cell migration, while the dual silencing of FN1 reverses these effects. Analysis of patient biopsies and xenograft models revealed a reciprocal pattern of PIM2 and FN1 expression. These findings delineate a TAM-controlled signaling circuit that integrates inflammatory cues with adhesion loss and invasive behavior, highlighting the IL6-STAT3-PIM2-cMyc-FN1 axis as a potential target in MM therapy.

Cell adhesion; Epithelial-mesenchymal transition; Fibronectin 1; Multiple myeloma; PIM2 kinase; Tumor-associated macrophages.