Abstract
Better and sensitive biomarkers are needed to help understand the mechanism of disease onset, progression, prognosis and monitoring of the therapeutic response. Aim of this study was to identify the candidate circulating markers of chronic-phase chronic myeloid leukemia (CP-CML) manifestations, having potential to develop into predictive- or monitoring-biomarkers. A proteomic approach, two-dimensional gel electrophoresis in conjunction with mass spectrometry (2DE-MS), was employed for this purpose. Based on the spot intensity measurements, six proteins were found to be consistently dysregulated in CP-CML subjects compared to the healthy controls [false discovery rate (FDR) threshold ≤0.05]. These were identified as α-1-antichymotrypsin, α-1-antitrypsin, CD5 molecule-like, stress-induced phosphoprotein 1, vitamin D binding protein isoform 1 and transthyretin by MS analysis [PMF score ≥79; data accessible via ProteomeXchange with identifier PXD002757]. Quantitative ELISA, used for validation of candidate proteins both in the pre-treated and nilotinib-treated CP-CML cases, demonstrate that CD5 molecule-like, transthyretin and alpha-1-antitrypsin may serve as useful predictive markers and aid in monitoring the response of TKI-based therapy (ANOVA p < 0.0001). Two of the circulating marker proteins, identified in this study, had not previously been associated with chronic- or acute-phase myeloid leukemia. Exploration of their probable association with CP-CML, in a larger study cohort, may add to our understanding of the disease mechanism besides developing clinically useful biomarkers in future.
Highlights
Better and sensitive biomarkers are needed to help understand the mechanism of disease onset, progression, prognosis and monitoring of the therapeutic response
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, which results from reciprocal translocation between chromosome 9 and 22 t(9;22) (q34;q11) [Philadelphia chromosome] generating BCR-ABL, a tyrosine kinase encoding oncogene[4]
From the pooled control and the individual chronic-phase chronic myeloid leukemia (CP-CML) samples, ~1300 gel spots were subjected to MALDI-TOF MS analysis, which led to the identification of 33 distinct proteins and/or their respective isoforms/subunits (Table 3)
Summary
Better and sensitive biomarkers are needed to help understand the mechanism of disease onset, progression, prognosis and monitoring of the therapeutic response. During the course of CML progression (chronic-, accelerated- and blast-crises phases), underlying gradual amplification of BCR-ABL-driven genomic instability and secondary modifications at genetic/epigenetic levels are believed to have major knock-on effect in altering and activating the expression of different mitogenic, anti-differentiating and anti-apoptotic modulators and mediators with resultant profound influence on the proteome profiles[4,5,6] Analysis of these altered protein profiles in patients and their healthy counterparts are likely to assist in keeping track of the underlying concealed perturbations while expediting the search for novel diagnostic biomarkers and therapeutic targets of the disease
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