Open Access

Cosima Drewes, Cristina López, Nnamdi Okeke, Billy Jebaraj, Christoph Wiegreffe, Isabelle Kraus, Sina Hillebrecht, Amani Awada, Susanne Bens, Emil Chteinberg, Barbara Eichhorst, Sarah Datismann, Martin J. S. Dyer, Anja Fischer, Kirsten Fischer, Selina Glaser, Michael Hallek, Helene Kretzmer, Anja Mottok, Dominick Pfaff, Karoline Schnitzler, Jan P. Meier-Kolthoff, Matthias Schlesner, Christof Schneider, Stefan Britsch, Ole Ammerpohl, Stephan Stilgenbauer, Eugen Tausch, Reiner Siebert

• 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 casesActivation 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.…