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

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Authors	STAMATOPOULOS B. SMITH T. CROMPOT E. PIETERS K. CLIFFORD R. MRÁZ Marek ROBBE P. BURNS A. TIMBS A. BRUCE D. HILLMEN P. MEULEMAN N. MINEUR P. FIRESCU R. MAEREVOET M. DE WILDE V. EFIRA A. PHILIPPE J. VERHASSELT B. OFFNER F. SIMS D. HEGER A. DREAU H. SCHUH A.
Year of publication	2018
Type	Article in Periodical
Magazine / Source	Clinical cancer research
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://clincancerres.aacrjournals.org/content/24/20/5048
Doi	http://dx.doi.org/10.1158/1078-0432.CCR-18-0133
Keywords	B-CELL RECEPTOR; ZAP70 MESSENGER-RNA; GENE-EXPRESSION; IG; LIGATION; CLL; QUANTIFICATION; STIMULATION; REVEALS
Description	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 coexpressed 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 IgLV321 light chain usage defines a new subgroup of CLL patients with poor prognosis. (C) 2018 AACR.
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