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

Next-generation sequencing (NGS) studies have identified > 200 potential genetic drivers of chronic lymphocytic leukemia (CLL). Nevertheless, the prognostic and functional impact of numerous mutations remains elusive. Here, we assessed the clinical and biological implications of ZMYM3 mutations in CLL, a gene recurrently mutated in 2–4% of patients. NGS analyses of 487 CLL cases identified 32 ZMYM3 variants, of which 75% were loss-of-function. Notably, 70% of ZMYM3 -mutated patients harbored mutations in the NOTCH signaling pathway, predominantly affecting NOTCH1 (60%). Clinically, ZMYM3 variants were associated with a shorter time to first treatment in univariate and multivariate analyses (median: 35 vs 52 months; p = 0.010), and stratified the clinical outcome of early-stage cases (median: 48 vs 91 months; p = 0.016). Functionally, CRISPR/Cas9 models demonstrated that ZMYM3 mutations cooperate with NOTCH1 mutations to induce profound transcriptional dysregulation. Furthermore, RNA-sequencing of cellular models and CLL patient samples revealed that ZMYM3 mutations impact DNA damage response and histone acetylation, leading to reduced chromatin accessibility. Additionally, ZMYM3 mutations promoted apoptosis evasion through caspase downregulation, correlating this anti-apoptotic phenotype with higher sensitivity to BCL-XL inhibition in vitro and ex vivo . Overall, this work underscores the clinical relevance of ZMYM3 mutations and provides novel insights into their contribution to CLL pathophysiology.