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.
- 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
3rd ed, revised and expanded XIII, 868 s. : il. ; 26 cm
Immunology and allergy clinics of North America ; Vol. 13 No. 1
254 s. : obr., tab., přeruš.bibliogr.
Immunology and allergy clinics of North America, ISSN 0889-8561 vol. 7, no. 3, December 1987
xi, 355-509 s. : il., tab., grafy ; 23 cm
- MeSH
- alergie klasifikace diagnóza MeSH
- imunosupresiva MeSH
- imunoterapie MeSH
- Publikační typ
- sborníky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- alergologie a imunologie
Immunology and allergy clinics of North America, ISSN 0889-8561 vol. 7, no. 2, August 1987
x, 179-354 s. : tab. ; 23 cm
- MeSH
- alergeny imunologie MeSH
- alergie klasifikace diagnóza MeSH
- Publikační typ
- sborníky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- alergologie a imunologie
