ZMYM3 mutations modulate histone acetylation and cooperate with NOTCH1 mutations in chronic lymphocytic leukemia

ZMYM3 mutations have been recurrently identified in chronic lymphocytic leukemia (CLL) patients at diagnosis. However, their clinical relevance and functional implications remain poorly defined. Here, we comprehensive characterize the clinical and translational impact of ZMYM3 mutations in CLL. Next-Generation Sequencing (NGS) analyses of 487 CLL cases identified 32 ZMYM3 variants, predominantly manifested as loss-of-function variants. ZMYM3-mutated patients showed a strong enrichment of NOTCH signaling pathway alterations, with 60% harboring NOTCH1 mutations. Clinically, ZMYM3 variants were associated with a higher treatment requirement and a significantly shorter time to first treatment (median: 35 vs 52 months; p=0.010), and stratified clinical outcome in early-stage cases (median: 48 vs 91 months; p=0.016). Multivariable analysis confirmed ZMYM3 mutations as an independent adverse prognostic factor. Using CRISPR/Cas9-edited CLL cells, we demonstrate that ZMYM3 mutations cooperate with NOTCH1 mutations to induce widespread transcriptional dysregulation. Moreover, RNA-sequencing of cellular models and CLL patient samples further revealed that ZMYM3 mutations impact histone acetylation, resulting in reduced chromatin accessibility. Functionally, ZMYM3 mutations promoted apoptosis evasion through caspase downregulation. Importantly, primary ZMYM3-mutated CLL cells exhibited increased sensitivity to BCL-XL inhibition and ibrutinib. Overall, this work establishes the clinical relevance of ZMYM3 mutations and provides novel insights into their contribution to CLL pathophysiology.