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

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent relapse and refractory disease (RRMM).
• The molecular mechanisms underlying clonal evolution, immune evasion, and therapy response in MM remain poorly understood.
• Identifying novel therapeutic targets is crucial for improving outcomes in high-risk MM patients.

Purpose of the Study:

• To investigate the role of PRKD2 in MM pathogenesis, immune escape, and therapy response.
• To explore the therapeutic potential of targeting PRKD2 or using axitinib in MM.

Main Methods:

• Analysis of bulk and single-cell RNA sequencing data from MM patients.
• Gene expression profiling, WGCNA, enrichment analysis, and immune deconvolution.
• In vitro studies involving PRKD2 knockdown/overexpression and axitinib treatment in MM cell lines.

Main Results:

• PRKD2 is uniformly upregulated in MM, correlating with disease progression, poor survival, and immune evasion.
• PRKD2 knockdown reduces proliferation and restores immune recognition, while overexpression promotes immune suppression and a pro-tumorigenic macrophage phenotype.
• PRKD2 expression positively correlates with axitinib sensitivity, and axitinib treatment modulates PRKD2-driven phenotypes.

Conclusions:

• PRKD2 integrates secretory stress, stem-like programs, and immune evasion, driving aggressive MM.
• PRKD2 inhibition or axitinib-based therapies, potentially combined with proteasome inhibitors, show promise for high-risk MM.
• Targeting PRKD2 represents a novel therapeutic vulnerability in multiple myeloma.