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

ZMYM3 mutations have been recurrently identified in patients with chronic lymphocytic leukemia (CLL) at diagnosis. However, their clinical relevance and functional implications remain poorly defined. In this study, we comprehensively characterize the clinical and translational impact of ZMYM3 mutations in CLL. Next-generation sequencing analyses of 487 CLL patients identified 32 ZMYM3 variants, which predominantly manifested as loss-of-function variants. Patients with ZMYM3-mutated CLL 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 53 months; P = .010) and stratified clinical outcome among early-stage patients (median, 48 vs 108 months; P = .002). Multivariable analysis confirmed ZMYM3 mutations as an independent adverse prognostic factor. Using CRISPR/Cas9-edited CLL cells, we demonstrated that ZMYM3 mutations cooperate with NOTCH1 mutations to induce widespread transcriptional dysregulation. Moreover, RNA-sequencing of cellular models and samples from patients with CLL 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 provide novel insights into their contribution to CLL pathophysiology.