ZMYM3 mutations modulate histone acetylation and cooperate with NOTCH1 mutations in chronic lymphocytic leukemia [ATAC-seq]

ABSTRACT: Recent advances in next-generation sequencing (NGS) have significantly expanded our understanding of the mutational landscape of chronic lymphocytic leukemia (CLL), identifying over 200 potential genetic drivers. Nevertheless, the prognostic and functional impact of numerous mutations remains elusive. In this study, through the integration of clinical, in vitro and ex vivo data, we assessed the clinical and biological implications of ZMYM3 mutations in CLL, a gene recurrently mutated in 2-4% of patients. NGS analyses in a cohort of 487 CLL cases identified 32 ZMYM3 variants, with 75% (24/32) characterized as loss-of-function mutations. Notably, 70% of ZMYM3-mutated patients harbored mutations in the NOTCH signaling pathway, predominantly in NOTCH1 (60%). In terms of clinical impact, in both univariate and multivariate analysis ZMYM3 variants were significantly associated with a shorter time to first treatment compared to control cases (median: 35 vs 52 months; p=0.010) and stratified the clinical outcome of early-stage CLL cases (median: 48 vs 91 months; p=0.016). In parallel, using CRISPR/Cas9 editing, we demonstrated that ZMYM3 mutations exhibit cooperative effects with NOTCH1 mutations, evidenced by a profound transcriptional dysregulation. In line, our findings revealed that ZMYM3 mutations reduce global histone H4 acetylation and modulate chromatin accessibility. Furthermore, at the functional level, ZMYM3 mutations compromise DNA damage repair mechanisms and promote apoptosis evasion by caspases downregulation, correlating this anti-apoptotic phenotype with higher sensitivity to BCL-XL inhibition. Overall, this work underscores the significance of ZMYM3 mutations in chromatin modification and its relevance in CLL prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274467 | GEO | 2026/08/19

REPOSITORIES: GEO