The biological and molecular relevance of upregulated NONO protein in multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells. Weidentified NONO, a key protein in paraspeckle (PS) biogenesis and NEAT1 stabilization, asa potential therapeutic target due to its high expression in MM patients and associationwith poor prognosis. Using gymnotic delivery of LNA-gapmeR, NONO silencing (NONO-KD) in human myeloma cell lines (HMCLs) impaired proliferation, induced apoptosis, andled to G0/G1 arrest, indicating disrupted cell cycle and deregulated progression intomitosis. NONO-KD enhanced sensitivity to bortezomib in resistant HMCLs and synergizedwith other MM treatments. Importantly, NONO silencing did not affect healthy PBMCs,suggesting specificity for MM cells. Transcriptomic analysis revealed the downregulation of pathways linked to chromatin remodelling and oncogenic signalling (WNT/β-cateninand NOTCH), largely overlapping with NEAT1-KD effects, observed in previousexperiments. However, data from the CoMMpass dataset identified NONO-exclusive andPS-unrelated roles in RNA splicing, protein trafficking, mitochondrial biogenesis and cell-matrix adhesion. These results highlight NONO as a key regulator of MM cell survival anda promising therapeutic target for the development of novel anti-MM therapeuticapproaches.