PYGO2 Identified as Key Driver of 1q21+ Multiple Myeloma Progression and Potential Therapeutic Target
核心洞察
PYGO2 (搜索) is significantly overexpressed in multiple myeloma (搜索) patients with 1q21 amplification, with expression levels positively correlating with copy number of the 1q21 region.
High PYGO2 (搜索) expression is associated with adverse cytogenetic features including del(13q) and t(4;14), and significantly shorter progression-free and overall survival in MM patients.
PYGO2 (搜索) knockdown in 1q21+ MM cell lines reduces proliferation through CCND1 (搜索) downregulation and H3K4me3 modulation, while overexpression accelerates cell cycle progression and enhances cell growth.
A team of researchers has identified PYGO2 (搜索), a transcriptional co-activator in the Wnt/β-catenin signaling pathway, as a key gene driving disease aggressiveness in multiple myeloma (搜索) (MM) patients harboring 1q21 amplification. The findings, published in Cancer Gene Therapy, demonstrate that PYGO2 is overexpressed in a copy number-driven fashion and plays a functional role in MM cell proliferation and cell cycle regulation.
The study, led by Nicolas Thomas Iannozzi and colleagues including Nicola Giuliani, analyzed gene expression in CD138+ plasma cells from MM bone marrow aspirates across multiple independent patient cohorts, including the CoMMpass dataset encompassing 847 unique patients.
PYGO2 (搜索) Overexpression Correlates with 1q21 Amplification and Poor Prognosis
Analysis of the GSE227907 database, comprising 29 primary CD138+ samples (11 smoldering MM and 18 newly diagnosed MM), revealed that PYGO2 (搜索) was significantly upregulated in 1q21+ patients compared to controls (p = 0.0008). A strong positive correlation was observed between PYGO2 gene expression and 1q21 copy number (p < 0.0001, r = 0.6738).
These findings were validated in an independent cohort of 43 patients, confirming significant PYGO2 (搜索) overexpression in 1q21+ patients (p = 0.0011). Immunohistochemistry on bone biopsies further demonstrated significantly higher nuclear protein expression of PYGO2 in 1q21+ patients compared to controls (p = 0.0003).
Analysis of the CoMMpass dataset confirmed the significant correlation between PYGO2 (搜索) gene expression and PYGO2 locus copy number (p < 2.2e-16, r = 0.39). When patients were stratified by PYGO2 expression quartiles, those in the highest expression quartile (Q1) exhibited significantly poorer progression-free survival (p = 0.0045) and overall survival (p = 0.0011) compared to patients with lower expression.
Furthermore, high PYGO2 (搜索) expression was significantly associated with adverse cytogenetic features, including 13q loss and t(4;14), while hyperdiploidy and t(11;14) were more frequent in patients with low PYGO2 expression.
Functional Role of PYGO2 (搜索) in MM Cell Proliferation
Analysis of the DepMap dataset revealed that MM cell lines express higher levels of PYGO2 (搜索) mRNA compared to other hematological and solid cancers, with MM lines carrying 1q21+ expressing more PYGO2 than those without the amplification. PYGO2 mRNA levels increased with PYGO2 locus copy number (p = 0.017, r = 0.56).
Knockdown of PYGO2 (搜索) using shRNA in three 1q21+ human myeloma cell lines (JJN3, OPM2, and U266) significantly reduced cell growth over nine days compared to scramble controls. This reduction in proliferation was accompanied by decreased mRNA levels of CCND1 (搜索), a key downstream target of the Wnt/β-catenin pathway.
Mechanistically, the researchers observed that PYGO2 (搜索) knockdown reduced protein expression of H3K4me3, a histone modification present on the CCND1 (搜索) promoter. "PYGO2 can regulate the H3K4me3 level and, consequently, the CCND1 expression levels, affecting MM cell proliferation," the authors noted.
Transcriptional and Cell Cycle Effects
RNA-sequencing of JJN3 cells following PYGO2 (搜索) knockdown identified 452 differentially expressed genes, with 143 upregulated and 309 downregulated. PYGO2 depletion reduced expression of several Wnt/TCF targets including CCND1 (搜索), JUN, CCND3, and AXIN2, while producing a shift in the replication-stress and DNA damage response transcriptome toward increased expression of checkpoint genes such as RAD51, CHEK1, CHEK2, H2AFX, and FANCD2.
Gene set enrichment analysis showed that hedgehog signaling, epithelial-mesenchymal transition, interferon-γ response, inflammatory response, and TGF-β signaling pathways were enriched in cells with higher PYGO2 (搜索) expression.
Cell cycle analysis revealed distinct effects across cell lines. In JJN3 cells, PYGO2 (搜索) knockdown significantly increased the Sub G0 fraction, indicating enhanced cell death. In OPM2 cells, knockdown led to G0/G1 phase arrest with a significant reduction in the G2 phase population.
Conversely, PYGO2 (搜索) overexpression in the 1q21 wild-type OCI-MY5 cell line increased CCND1 (搜索) expression, accelerated cell cycle progression with a significant reduction in G0/G1 phase cells and increase in S phase cells, and enhanced overall proliferation.
Implications for Proteasome Inhibitor Sensitivity
The study also investigated the role of PYGO2 (搜索) in response to proteasome inhibitors. PYGO2 knockdown significantly increased sensitivity to both carfilzomib and bortezomib in 1q21+ cell lines, while PYGO2 overexpression in OCI-MY5 cells reduced response to carfilzomib treatment.
"These results suggest that PYGO2 (搜索) could be a target for a personalized approach in the subgroup of MM patients with 1q21+," the authors concluded, noting that efforts to disrupt PYGO2's interaction with the Wnt transcriptional machinery or its chromatin-binding domains could provide a basis for therapeutic strategy.
The study represents the first demonstration of PYGO2 (搜索) overexpression in MM patients with 1q21 amplification and its functional role in promoting tumor vitality and proliferation, opening new avenues for targeted therapy in this high-risk patient population.