Abstract
Approximately 1% of chronic lymphocytic leukemia (CLL) cases harbor a translocation juxtaposing the immunoglobulin heavy chain (IGH) and B-cell lymphoma 3 (BCL3) loci. Aiming at comprehensive molecular characterization of IGH::BCL3-positive B-cell neoplasms, we here investigated samples from 84 patients using fluorescence in situ hybridization (FISH), whole-genome and targeted sequencing, and DNA methylation analyses. Junctional sequences obtained in 27 patients showed breakpoints upstream of BCL3 in all CLL cases. IGH breaks were presumably driven by aberrant class-switch recombination in 26/27 cases, frequently involving IGHA (12/26). Notably, 95% (78/82) of patients carried an unmutated IGHV with significant CLL stereotype subset #8 enrichment. Trisomy 12 (61%, 51/83) and mutations affecting NOTCH1 (32%, 25/79), BRAF (14%, 11/79), and FBXW7 (14%, 11/79) were frequent aberrations. DNA methylation analysis assigned 77% (51/66) of patients with IGH::BCL3-translocation with at least 60% tumor cell content to the naive B-cell-like group but unraveled a distinct and during follow-up stable signature resembling in part plasma cell-like epigenetic features. A binary DNA methylation classifier using 20 CpGs could distinguish IGH::BCL3-translocated CLL samples from other CLL subtypes. In an efficacy cohort of 3832 previously untreated patients from GCLLSG trials, IGH::BCL3 was associated with shorter progression-free survival (PFS) and overall survival (OS) in 28 patients when treated with chemoimmunotherapy, but not in those receiving venetoclax. Our findings highlight the genetic and epigenetic homogeneity of IGH::BCL3-translocated CLL samples and their differences from other types of CLL, suggesting IGH::BCL3 leukemic B-cell neoplasms to be a biological distinct type within the spectrum of mature lymphatic leukemia/CLL.