Publication details
The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
| Authors | |
|---|---|
| Year of publication | 2018 |
| Type | Article in Periodical |
| Magazine / Source | Clinical cancer research |
| MU Faculty or unit | |
| 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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