IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia.
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ABSTRACT:
SUBMITTER: Nadeu F
PROVIDER: S-EPMC10726246 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia.
Syrykh Charlotte C Pons-Brun Berta B Russiñol Núria N Playa-Albinyana Heribert H Baumann Tycho T Duran-Ferrer Martí M Kulis Marta M Carbó-Meix Anna A Mozas Pablo P Alcoceba Miguel M González Marcos M González Marcos M Navarro-Bailón Almudena A Colado Enrique E Payer Ángel R ÁR Aymerich Marta M Terol María J MJ Lu Junyan J Knisbacher Binyamin A BA Knisbacher Binyamin A BA Hahn Cynthia K CK Ruiz-Gaspà Sílvia S Enjuanes Anna A Wu Catherine J CJ Getz Gad G Zenz Thorsten T López-Guillermo Armando A Martín-Subero José I JI Colomer Dolors D Delgado Julio J Campo Elías E Nadeu Ferran F
Blood advances 20231201 23
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Project description:B-cell receptor (BCR) signaling is crucial for chronic lymphocytic leukemia (CLL) biology. IGLV3-21-expressing B cells may acquire a single point mutation (R110) that triggers autonomous BCR signaling, conferring aggressive behavior. Epigenetic studies have defined 3 CLL subtypes based on methylation signatures reminiscent of naïve-like (n-CLL), intermediate (i-CLL), and memory-like (m-CLL) B cells with different biological features. i-CLL carries a borderline IGHV mutational load and significantly higher use of IGHV3-21/IGLV3-21. To determine the clinical and biological features of IGLV3-21R110 CLL and its relationship to these epigenetic subtypes, we characterized the immunoglobulin gene of 584 CLL cases using whole-genome/exome and RNA sequencing. IGLV3-21R110 was detected in 6.5% of cases: 30 (38%) of 79 i-CLLs, 5 (1.7%) of 291 m-CLLs, and 1 (0.5%) of 189 n-CLLs. All stereotype subset 2 cases carried IGLV3-21R110, whereas 62% of IGLV3-21R110 i-CLL cases had nonstereotyped BCR immunoglobulins. IGLV3-21R110 i-CLL had a significantly higher number of SF3B1 and ATM mutations and total number of driver alterations. However, the R110 mutation was the sole alteration in 1 i-CLL and was accompanied only by del(13q) in 3. Although IGHV mutational status varied, IGLV3-21R110 i-CLL transcriptomically resembled n-CLL/unmutated IGHV CLL with a specific signature including WNT5A/B overexpression. In contrast, i-CLL lacking IGLV3-21R110 mirrored m-CLL/mutated IGHV. Patients with IGLV3-21R110 i-CLL had a short time to first treatment and overall survival similar to those of n-CLL/unmutated IGHV patients, whereas patients with non-IGLV3-21R110 i-CLL had a good prognosis similar to that of patients with m-CLL/mutated IGHV. IGLV3-21R110 defines a CLL subgroup with specific biological features and an unfavorable prognosis independent of IGHV mutational status and epigenetic subtype.
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Project description:BackgroundThe clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified.MethodsIn this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts.ResultsA robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression.ConclusionTFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis.
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