title: Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups.
abstract: Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a (1)H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n=29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n=9). Differences in metabolic profiles between unmutated (UM-IGHV; n=10) and mutated IGHV (M-IGHV; n=19) patients were determined using partial least square discriminatory analysis (PLS-DA; R(2)=0.74, Q(2)=0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with disease-related metabolic profiles. Our results highlight the usefulness of (1)H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.
authors.affiliation: Structural Biology Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: D A
authors.initials: DA
authors.lastname: MacIntyre
authors.forename: B
authors.initials: B
authors.lastname: Jiménez
authors.forename: E Jantus
authors.initials: EJ
authors.lastname: Lewintre
authors.forename: C Reinoso
authors.initials: CR
authors.lastname: Martín
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
authors.forename: C García
authors.initials: CG
authors.lastname: Ballesteros
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Mayans
authors.forename: M
authors.initials: M
authors.lastname: Spraul
authors.forename: J
authors.initials: J
authors.lastname: García-Conde
authors.forename: A
authors.initials: A
authors.lastname: Pineda-Lucena
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000145:classification / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human