Journal
CLINICAL CANCER RESEARCH
Volume 24, Issue 20, Pages 5048-5057Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-0133
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Funding
- F.R.S.-FNRS (Fonds National de la Recherche Scientifique) of Belgium
- the David and Alice Van Buuren Fund
- the Fonds IRIS-Recherche
- Les Amis de l'Institut Jules Bordet
- Wallonie-Bruxelles International World (WBI.World)
- Bekales Fundation
- foundation Lambeau-Marteaux
- National Institute for Health Research (NIHR)
- Oxford Biomedical Research Centre (BRC)
- Ministry of Health of the Czech Republic [16-29622A]
- MRC [MC_PC_15065] Funding Source: UKRI
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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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