Novel Autoregulation of PIM2 Expression Sustains Plasma Cell Survival in Multiple Myeloma 2916

Description Multiple myeloma (MM), a malignancy of plasma B cells, remains largely incurable despite therapeutic advances. PIM2 kinase overexpression is a characteristic feature of MM progression, yet the mechanisms controlling its elevated expression remain poorly understood. Through integrated genomic and molecular analyses, we discovered that PIM2 unexpectedly functions as a transcriptional regulator through a previously unexplored kinase-independent mechanism. Analysis of the PIM2 promoter revealed a critical regulatory hub where PIM2 and MYC co-localize at genomic loci to regulate gene expression. Remarkably, PIM2 kinase-dead mutants maintained full regulatory function, demonstrating that this transcriptional control operates independently of kinase activity. RT-qPCR analysis across multiple MM cell lines confirmed that both kinase-active and kinase-dead PIM2 enhanced endogenous PIM2 expression. Using PIM2-selective inhibitors, JP11646 (targeting both functions), CpdA (kinase-independent), and AZD1208 (kinase-dependent), we show a novel PIM2 autoregulatory paradigm. Our findings reveal that PIM2 maintains its own expression through kinase-independent transcriptional control while promoting cell survival through kinase-dependent pathways, establishing a novel circuit in malignant plasma cells. This work provides fundamental insights into immune cell gene regulation and suggests innovative therapeutic strategies targeting the dual functions of PIM2 in MM.