Abstract / Summary
Abstract Background ZNF292 alterations are recurrently detected in patients with chronic lymphocytic leukemia (CLL), occurring in 3%-6% of patients as mutations and in 2% as 6q deletions. Although preliminary evidence suggested an independent prognostic role for ZNF292 mutations, their specific clinical relevance in early-stage CLL and the underlying biological mechanisms remain poorly defined. Methods 488 CLL patients were analyzed using targeted Next-Generation Sequencing (NGS) to characterize the landscape and clinical significance of ZNF292 mutations. CRISPR/Cas9-genome editing was employed to introduce the most prevalent ZNF292 variants into CLL cellular models. Their biological and functional implications were evaluated by integrating RNA-sequencing data from these isogenic cellular models with transcriptomic data from primary patient samples, complemented by functional validation and drug response assays. Results ZNF292 mutations were associated with shorter time to first treatment (TTFT; median 25 vs. 52 months, P = 0.009) and inferior overall survival (OS, median 93 vs. 148 months, P = 0.004). Importantly, when restricting the analyses to early-stage cases, ZNF292 alterations were independently associated with shorter TTFT and OS, identifying a high-risk subgroup. Mechanistically, transcriptomic analyses revealed that ZNF292 mutations suppress global protein biosynthesis and modulate cell cycle progression in both primary CLL samples and CRISPR/Cas9-edited cells. Furthermore, ZNF292 deficiency impaired replication stress responses via defective CHK1 activation, resulting in DNA damage accumulation. Evaluating potential therapeutic vulnerabilities, ZNF292 -mutated cells exhibited enhanced in vitro sensitivity to ibrutinib and venetoclax. Conclusions Our findings propose ZNF292 alterations as an independent prognostic factor in early-stage CLL and unveil their role in disease progression.