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

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 analyses, 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).