Supplementary Data from The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study

Stamatopoulos, Basile; Smith, Thomas; Crompot, Emerence; Pieters, Karlien; Clifford, Ruth; Mraz, Marek; Robbe, Pauline; Burns, Adam; Timbs, Adele; Bruce, David; Hillmen, Peter; Meuleman, Nathalie; Mineur, Philippe; Firescu, Radu; Maerevoet, Marie; De Wilde, Virginie; Efira, André; Philippé, Jan; Verhasselt, Bruno; Offner, Fritz; Sims, David; Heger, Andreas; Dreau, Hélène; Schuh, Anna

doi:10.1158/1078-0432.22474742.v1

10780432ccr180133-sup-195436_3_supp_4820437_pn7lt5.docx (7.93 MB)

Supplementary Data from The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study

journal contribution

posted on 2023-03-31, 21:41 authored by Basile Stamatopoulos, Thomas Smith, Emerence Crompot, Karlien Pieters, Ruth Clifford, Marek Mraz, Pauline Robbe, Adam Burns, Adele Timbs, David Bruce, Peter Hillmen, Nathalie Meuleman, Philippe Mineur, Radu Firescu, Marie Maerevoet, Virginie De Wilde, André Efira, Jan Philippé, Bruno Verhasselt, Fritz Offner, David Sims, Andreas Heger, Hélène Dreau, Anna Schuh

Supplementary Data Figure S1. Determination of IgLV3-21 positivity by real-time PCR. Supplementary Data Figure S2: CLL-OS analysis including only CLL-related deaths. Supplementary Data Figure S3. Validation of the poor prognosis associated with IgLV3-21 usage in population C. Supplementary Data Figure S4. Validation of the poor prognosis of IgLV3-21 usage in population D. Supplementary Data Figure S5: prognostic impact of IgLV3-21 usage in the different CLL-IPI subgroups. Supplementary Data Figure S6. Immunogenetic features of IgLV3-21 patients. Supplementary Data Figure S7. CXCR4 surface expression is downregulated in IgLV3-21 patients.

Funding

Ministry of Health of the Czech Republic

History

ARTICLE ABSTRACT

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.