Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of theIGHtranslocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients withIGHrearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations inNOTCH1,IGLL5,POT1,BCL2,FBXW7,ZMYM3,MGA,BRAFandHIST1H1Egenes. Interestingly,BCL2andFBXW7mutations were significantly associated with this subgroup and almost half ofBCL2,IGLL5andHISTH1Emutations reported were previously identified in non-Hodgkin lymphomas. Notably,IGH/BCL2rearrangements were associated with a lower mutation frequency and carriedBCL2andIGLL5mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1,SF3B1andTP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor whenNOTCH1,SF3B1,TP53,BIRC3andBRAFwere also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status ofIGHby FISH analysis to refine the risk-stratification CLL model.