A novel chromatographic approach to investigate thio-metabolome role as potential prognostic and/or diagnostic biomarker in GvHD

MAIN AREA: Metabolic alteration in transplantation

Keywords: GvHD, GSH, hematopoietic stem cells transplantation, HPLC 

Background. The cellular metabolome observation in acute myeloid leukemia cells treated with FLT3 inhibitors showed the significant alterations of central carbon metabolism: glutathione (GSH) metabolism is compromised by FLT3 inhibition. GSH with glutamine and serine is essential for maintaining the malate-aspartate shuttle in T lymphocytes. GSH and thio-compounds metabolism are modified in hemathopoietic stem cells transplantation (HSCT) patients with patients with chronic graft vs. host disease (GvHD). Latest evidences show that serum cysteine is related with clinical progress of chronic GVDH. Thio-compound redox imbalance causes up-regulation of inflammatory cytokines: GSH has an essential role in oxidative stress damage response and in apoptotic transduction signal.

Hypothesis. The study of kinetic and thermodynamic bond of chemical reactions involving GSH and other thio-metabolites, such as methionine, cystine, cystathionine and homocysteine, could be useful in the evaluation of hematological pathologies.

Aims. We aim to GSH and related metabolites has an essential role in oxidative stress damage response and in metabolic pathway involved in apoptotic transduction signal.

Experimental Design. The present project will be conducted on peripheral blood samples (PBMCs) collected from HSCT patients. On samples different analyses will be performed: (1) immunomagnetic automatic sorter analyses, functional assays and metabolomic analysis; (2) genetic analysis on patient DNA obtained from blood samples; (3) in vitro culture experiments on patients PBMCs.

Expected Results. We aim to find prognostic and diagnostic biomarker for clinical monitoring GvDH in pre/post HSCT patients and to validate the analytical methods implemented during the study.

Impact on cancer. The imbalance GSH biosynthesis, and then cellular homeostasis, could influence pathological conditions of cellular metabolism, underlying GvHD inflammation. This approach could lead to identify target metabolites useful in clinical diagnosis and prognosis of GvHD state, with the possible relapse of an improvement in the quality of life for patients suffering from onco-hematological pathologies.

This study protocol has been approved by the Local Ethic Committee (practice number 15/2020 “GSH19”).