Next-generation leukemia diagnostics: Integrating LC-MS/MS proteomics with liquid biopsy platforms

Abstract

Diagnosing leukemia often depends on invasive bone marrow biopsies, which can be painful and may fail to detect the early stages of the disease. Liquid biopsy, a minimally invasive method that analyzes circulating biomarkers in blood, has emerged as a powerful tool for the early detection of leukemia. Among emerging technologies, liquid chromatography-tandem mass spectrometry (LC-MS/MS) enables high-throughput and sensitive profiling of blood-based proteins, thereby creating new opportunities for biomarker discovery. This mini-review highlights the clinical potential of LC-MS/MS in liquid biopsy for leukemia, with a focus on T-cell acute lymphoblastic leukemia (T-ALL). Recent proteomic studies have identified distinct protein signatures in the blood of T-ALL patients, such as XRRA1, CPNE4, and S100A8, which show substantial diagnostic value. We also address similar applications in acute myeloid leukemia (AML), the challenges of clinical translation, and the future integration of proteomics with multi-omics diagnostic platforms. Importantly, we discuss the limitations of current studies (e.g., small cohorts, limited diversity, and reproducibility issues) and the path toward clinical implementation, including validation in larger trials, regulatory considerations, cost-effectiveness, and the need for standardized protocols. LC-MS/MS-driven liquid biopsy represents a promising advancement toward earlier, less invasive, and more precise leukemia diagnostics, provided that robust validation and harmonization efforts are successful.

Keywords: Biomarker discovery; Circulating protein biomarkers; LC-MS/MS; Leukemia diagnosis; Liquid biopsy; Multi-omics; Proteomics; T-ALL.

Fig. 1

Liquid Biopsy Workflow and Multi-Omics Analysis in Leukemia Schematic representation of the liquid biopsy workflow for leukemia detection. (1) Comparison between normal blood and leukemic blood showing the presence of abnormal cancerous lymphocytes. (2) Blood draw as a minimally invasive method to obtain a sample for analysis. (3) Collection of peripheral blood, followed by multi-layered sample analysis, including circulating cancer cells, epigenetic modifications, point mutations, chromosomal abnormalities, gene amplifications/deletions, protein expression/phosphorylation, and in vivo/in vitro culture systems. These analyses offer a comprehensive molecular overview of leukemia, enabling early diagnosis and personalized monitoring.

Fig. 2

Proteomic Workflow Using LC-MS/MS for Biomarker Discovery Overview of the LC-MS/MS-based proteomic workflow used for leukemia biomarker discovery. Protein samples are obtained from gel or solution and subjected to proteolysis to generate peptides. These peptides are then analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The resulting spectra are matched to protein databases for identification and quantification, enabling high-throughput, unbiased discovery of differentially expressed proteins in patient samples.