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The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study
B. Stamatopoulos, T. Smith, E. Crompot, K. Pieters, R. Clifford, M. Mraz, P. Robbe, A. Burns, A. Timbs, D. Bruce, P. Hillmen, N. Meuleman, P. Mineur, R. Firescu, M. Maerevoet, V. De Wilde, A. Efira, J. Philippé, B. Verhasselt, F. Offner, D. Sims,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, multicentrická studie, práce podpořená grantem
Grantová podpora
NV16-29622A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
NLK
Free Medical Journals
od 1995 do Před 1 rokem
Freely Accessible Science Journals
od 1995
Open Access Digital Library
od 1995-01-01
Open Access Digital Library
od 1995-01-01
- MeSH
- chromozomální aberace MeSH
- chronická lymfatická leukemie diagnóza genetika mortalita MeSH
- genová ontologie MeSH
- klinické zkoušky jako téma MeSH
- lehké řetězce imunoglobulinů genetika MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery MeSH
- peptidy genetika MeSH
- prognóza MeSH
- regulace genové exprese u leukemie MeSH
- sekvenční analýza DNA MeSH
- stanovení celkové genové exprese MeSH
- transkriptom MeSH
- variabilní oblast imunoglobulinu genetika MeSH
- výpočetní biologie metody MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
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.
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 Ghent University Hospital Ghent Belgium
Hematology Department CHU Ambroise Paré Mons Belgium
Hematology Department Hôpital Erasme Brussels Belgium
Hematology Department Jules Bordet Institute Brussels Belgium
Molecular Diagnostic Centre Oxford University Hospitals Oxford United Kingdom
St James' Institute of Oncology St James' University Hospital Leeds United Kingdom
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- $a Stamatopoulos, Basile $u Laboratory of Clinical Cell Therapy, Jules Bordet Institute, ULB-Research Cancer Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium. bstamato@ulb.ac.be. Molecular Diagnostic Centre, Oxford University Hospitals, Oxford, United Kingdom. Nuffield Department of Laboratory Sciences, University of Oxford, Oxford, United Kingdom.
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- $a The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study / $c B. Stamatopoulos, T. Smith, E. Crompot, K. Pieters, R. Clifford, M. Mraz, P. Robbe, A. Burns, A. Timbs, D. Bruce, P. Hillmen, N. Meuleman, P. Mineur, R. Firescu, M. Maerevoet, V. De Wilde, A. Efira, J. Philippé, B. Verhasselt, F. Offner, D. Sims, A. Heger, H. Dreau, A. Schuh,
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