The spectrum of immunoglobulin heavy chain enhancer hijacking in chronic lymphocytic leukemia

Activation of oncogenes by hijacking immunoglobulin gene loci ( IG ) enhancers via chromosomal translocation is a common pathogenetic mechanism in B-cell malignancies, affecting 5–10% of chronic lymphocytic leukemia (CLL). The oncogenic partners in many of these cases remain unidentified. Therefore, we conducted a comprehensive analysis of 144 CLL samples with IGH- translocation excluding IGH :: BCL2 , IGH :: CCND1 , IGH :: BCL3 and IGH :: MYC . By combining fluorescence in situ hybridization (FISH) with whole-genome, targeted sequencing, and RNA expression profiling, we identified 25 IG -translocation partners; 12 were previously unreported. Of 142 cases, 107 (75%) displayed an unmutated IGHV . Genetic profiling showed a heterogenous distribution of chromosomal aberrations and recurrently mutated genes across the groups. Of 41 informative cases, 32 (78%) exhibited breakpoints driven by aberrant class-switch recombination (CSR), with prominent involvement of IGHM (9/41) and IGHG3 (9/41). Three cases with unmutated IGHV carried a juxtaposition of the IGH locus 5’ to the intact NKX2.6 gene in chromosome 8p21.2 due to illegitimate VDJ recombination, associated with significant ectopic upregulation of NKX2.6 transcriptional expression (FDR < 0.001, logFC: 15). Similarly, METRNL , located at the telomere of chromosome 17q25, was identified as a translocation partner gene in four cases. Our findings expand the spectrum of the oncogenic translocation partners targeting IGH in CLL.