Abstract
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.