Investigation of lncRNA expression in newly diagnosed multiple myeloma reveals a LINC01432-CELF2 axis as an inhibitor of apoptosis.

Abstract

Multiple myeloma (MM) is an incurable malignancy of plasma cells, with over 35,000 new cases diagnosed annually in the United States. Despite an expanding arsenal of approved therapies, nearly all patients relapse, and mechanisms underlying disease progression remain poorly understood. In particular, the role of long non-coding RNAs (lncRNAs) in MM progression and treatment response is largely unexplored. To address this gap, we performed transcriptome sequencing of newly diagnosed MM (NDMM) patient samples and compared individuals with short progression-free survival (PFS; <24 months) to those with prolonged PFS (>24 months) following standard first-line therapy. We identified 157 lncRNAs upregulated in patients with short PFS, and prioritized the most significantly upregulated transcript, LINC01432, for functional characterization. CRISPR-mediated knockdown of LINC01432 expression results in upregulation of genes associated with interferon-α/γ responses and increases apoptosis. Targeting LINC01432 with locked nucleic acid antisense oligonucleotides also induces apoptosis, which can be rescued by LINC01432 overexpression. Mechanistically, we discovered that LINC01432 binds the RNA-binding protein CELF2 directly. Transcriptomic analysis following depletion of either LINC01432 or CELF2 revealed 108 overlapping target genes, indicating that this lncRNA-protein complex regulates transcriptional programs governing immune activation, stress response, and cell survival. In summary, this study identified lncRNAs associated with NDMM and characterized LINC01432 as a critical regulator of MM cell survival, acting in complex with CELF2 to repress pro-apoptotic and immune response pathways. These findings highlight LINC01432 as a potential therapeutic target for overcoming resistance in MM.