Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)–associated T-cell malignancy with generally poor prognosis. Although only ∼5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor receptor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch’s t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL.

ORP4L is a prerequisite for the induction of T-cell leukemogenesis associated with human T-cell leukemia virus 1

“…There are an estimated 5 to 20 million human T-cell leukemia virus 1 (HTLV-1) infected individuals worldwide, and 3-5% of these carriers progress to deadly adult T-cell leukemia (ATL) with a median survival time of 2 to 6 months [1][2][3] . HTLV-1 directly infects peripheral T-cells and its oncoprotein Tax induces the malignant transformation of these cells 4,5 .…”

In-Depth Serum Proteomics by DIA-MS with In Silico Spectral Libraries Reveals Dynamics during the Active Phase of Systemic Juvenile Idiopathic Arthritis

“…In recent years, the proteome analysis of clinical samples using mass spectrometry (MS) has been attracting attention as a powerful tool for elucidating pathological conditions, identifying disease-related proteins as candidate biomarkers, and searching for drug targets. − In particular, serum represents an important clinical sample that can be collected in a minimally invasive manner, which is widely used in clinical practice for biochemical tests and biomarker measurements. The advantages of serum are its simplicity of collection and ease of storage.…”

Application of Cancer Cell Line Encyclopedia for Measuring Correlation Between Transcriptomics and Proteomics as a Guide for System-level Insights

“…The SomaScan platform simultaneously measures more protein targets than any other affinity-reagent technique existing at the time of publication; consequently, the ability to confirm SOMAmer reagents’ specificity to endogenous proteins with orthogonal strategies requires the integration of multiple additional techniques and the rate of orthogonal confirmations lags behind the number of measurements possible with SomaScan. We, along with the scientific community of SomaScan assay users, have approached SOMAmer reagent characterization through a variety of orthogonal methods including antibody techniques (ELISA, proximity extension assays) [24, 25], mass spectroscopy [26, 27], and comparisons to genetic techniques such as cis-protein quantitative trait locus detection (cis-pQTL) analysis [28, 29], and the mRNA correlations reported here (Fig. 5).…”