High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL.

Autor: Hengeveld PJ; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands.; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands., Kolijn PM; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands., Demmers JAA; Proteomics Center, Erasmus MC, Rotterdam, the Netherlands., Doff W; Proteomics Center, Erasmus MC, Rotterdam, the Netherlands., Dubois JMN; Department of Hematology and Experimental Immunology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands., Rijken M; Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands., Assmann JLJC; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands., van der Straten L; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands.; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands., Boiten HJ; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands., Gussinklo KJ; Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands., Valk PJM; Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands., Faber LM; Department of Hematology, Red Cross Hospital, Beverwijk, the Netherlands., Westerweel PE; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands., Kater AP; Department of Hematology and Experimental Immunology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands., Levin MD; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands., Langerak AW; Department of Immunology, Erasmus MC, Rotterdam, the Netherlands.
Jazyk: angličtina
Zdroj: HemaSphere [Hemasphere] 2023 Sep 15; Vol. 7 (10), pp. e951. Date of Electronic Publication: 2023 Sep 15 (Print Publication: 2023).
DOI: 10.1097/HS9.0000000000000951
Abstrakt: It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.
Competing Interests: JMND has received research funding from Roche/Genentech. APK has received personal fees from AbbVie, LAVA, Genmab, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb; and research funding from AbbVie, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb. M-DL has received personal fees from AbbVie, Janssen, and Roche; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. AWL has received research funding via an unrestricted grant from Roche-Genentech and speaker-fees from Janssen. All the other authors have no conflicts of interest to disclose.
(Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
Databáze: MEDLINE
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