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

• Published in: HemaSphere Vol. 7; no. 10; pp. e951 - n/a
• Main Authors: Hengeveld, Paul J., Kolijn, P. Martijn, Demmers, Jeroen A.A., Doff, Wouter, Dubois, Julie M.N., Rijken, Melissa, Assmann, Jorn L.J.C., Straten, Lina, Boiten, Henk Jan, Gussinklo, Kirsten J., Valk, Peter J.M., Faber, Laura M., Westerweel, Peter E., Kater, Arnon P., Levin, Mark‐David, Langerak, Anton W.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lippincott Williams & Wilkins 01.10.2023; Wiley
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/HS9.0000000000000951

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.