Biomarker research · 2026
ZNF292 mutations impair RNA and protein biosynthesis defining an adverse prognostic subset in early-stage chronic lymphocytic leukemia.
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Rodríguez-Sánchez Alberto, Alonso-Gago María, Pérez-Carretero Claudia, Corchete-Sánchez Luis A, Miguel-García Cristina, Santos-Minguez Sandra, Villaverde-Ramiro Ángela, Queizán-Hernandez José Antonio, Rubio Araceli, Benito-Sánchez Rocío, Schiavo Federico Lo, Ghetti Martina, Simonetti Giorgia, Rodríguez-Vicente Ana E, Hernández-Rivas Jesús M, Quijada-Álamo Miguel
Аннотация
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.
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.