Single-cell and bulk transcriptomics uncovers PRKD2-driven tumor stemness and progression in multiple myeloma.

Multiple myeloma (MM) remains incurable, as most patients relapse or become refractory (RRMM), and the molecular nexus among clonal evolution, immune escape and therapy response remains unknown. Bulk RNA-seq from 24 MM to 6 matched marrows (subset of 132) plus single-cell datasets were analysed by differential expression, pseudotime, WGCNA, enrichment, immune deconvolution and GDSC drug screens. PRKD2 was knocked down (KD) or over-expressed (OE) in H929, 8226 and U266 cells. Viability (CCK-8) and apoptosis (Annexin V/7-AAD) were assessed after 48 h of axitinib (1.25-10 µM). PRKD2 was the sole gene uniformly up-regulated in newly diagnosed MM, RRMM and poor-survival cohorts, rising along the malignant plasma-cell trajectory. High PRKD2 aligned with ISS-III stage, elevated mRNAsi/EREG_mRNAsi and worse 5-year survival (38% vs. 73%, P = 0.012). PRKD2-KD reduced proliferation (~ 30%) and restored HLA-E, whereas PRKD2-OE suppressed antigen-presentation genes and polarised macrophages toward an IL-6/MERTK tumour-promoting phenotype. PRKD2-high marrow contained more naïve/memory B cells but fewer mature plasma cells. PRKD2 expression correlated positively with axitinib sensitivity (- log(10) IC(50), r = 0.68; P < 0.001). Experimentally, PRKD2-OE cells showed a 1.4-fold increase in axitinib-induced apoptosis, while PRKD2-KD cells were intrinsically pro-apoptotic and further sensitised; axitinib abolished the growth advantage conferred by PRKD2-OE. PRKD2 integrates secretory stress, stem-like programmes and immune evasion, driving aggressive MM yet exposing a vulnerability to VEGFR/PDGFR blockade. Direct PRKD2 targeting or axitinib-based combinations-including proteasome inhibition-deserve clinical evaluation for high-risk MM.