PYGO2 is overexpressed in multiple myeloma patients with 1q21 amplification, driving plasma cell proliferation and...

Chromosome 1q21 copy number alterations (1q21+) are among the most frequent secondary events in multiple myeloma (MM), correlating with poor prognosis and therapy resistance. However, the molecular drivers of this lesion remain poorly defined. Here, we identify PYGO2, a Wnt/β-catenin co-activator located on 1q21, as a critical effector of MM progression. Analysis of primary CD138⁺ plasma cells and public datasets revealed that PYGO2 expression is significantly increased in 1q21+ patients and correlates with chromosome 1q copy number. High PYGO2 levels were associated with adverse cytogenetics and shorter progression-free and overall survival. Functional studies showed that PYGO2 knockdown (KD) in 1q21+ cell lines impaired proliferation, induced cell cycle perturbation coupled with CCND1 downregulation and reduced H3K4me3 enrichment, while increasing Carfilzomib and Bortezomib sensitivity. Conversely, PYGO2 overexpression enhanced cell growth and proteasome inhibitor resistance. RNA-seq profiling of KD cells revealed coordinated suppression of canonical Wnt/TCF target genes involved in proliferation and reshaped the replication stress and DNA damage response transcriptome, suggesting enhanced replication stress. RNA-seq profiling of KD cells also revealed suppression of oncogenic and immunomodulatory pathways, suggesting a broader role in tumor-microenvironment crosstalk. Overall, our data establish PYGO2 as a previously unrecognized effector of 1q21-driven aggressiveness in MM and suggest that it represents a therapeutic vulnerability in high-risk 1q21+ MM patients.