Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements-similar to UM IgHV status-conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P < 0.0001).Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048-57. ©2018 AACR.

Central European Institute of Technology Masaryk University Brno Czech Republic

Computational Genomics Analysis and Training Program MRC Weatherall Institute of Molecular Medicine University of Oxford Oxford United Kingdom

Department of Clinical Chemistry Microbiology and Immunology Ghent University Hospital Ghent University Ghent Belgium

Department of Hemato oncology Centre Hospitalier Universitaire Brugmann Brussels Belgium

Department of Hemato Oncology Grand Hôpital de Charleroi Charleroi Belgium

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Internal Medicine Hematology Ghent University Hospital Ghent Belgium

Department of Oncology University of Oxford Oxford United Kingdom

Hematology Department CHU Ambroise Paré Mons Belgium

Hematology Department Hôpital Erasme Brussels Belgium

Hematology Department Jules Bordet Institute Brussels Belgium

Laboratory of Clinical Cell Therapy Jules Bordet Institute ULB Research Cancer Center Brussels Belgium

Molecular Diagnostic Centre Oxford University Hospitals Oxford United Kingdom

Nuffield Department of Laboratory Sciences University of Oxford Oxford United Kingdom

St James' Institute of Oncology St James' University Hospital Leeds United Kingdom

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