Novel Autoregulation of PIM2 Expression Sustains Plasma Cell Survival in Multiple Myeloma 2916
Year: 2025
Type: article
Abstract: 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. Funding Sources R01CA272852-01, Purdue University and Indiana University School of Medicine Medical-Scientist Training Program (MSTP), ResearchHub Fast Grant Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
Source: The Journal of Immunology
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416446940
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