Abstract
Deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer, however little is known about its processes in myelodysplastic syndromes (MDS). Using transcriptomic data of CD34+ cells from 159 MDS patients and 17 healthy donors, we selected 37 genes involved in cellular energetics and interrogated about its clinical and prognostic functions. Based on the low expression of ACLY, ANPEP, and PANK1, as well as high expression of PKM and SLC25A5, we constructed our Molecular-Based Score (MBS), that efficiently discriminated patients at three risks groups: favourable risk (n = 28; 3-year overall survival (OS): 100%); intermediate (n = 60; 76% [62–93%]) and adverse (n = 71; 35% [17–61%]). Adverse MBS risk was independently associated with inferior OS (HR = 10.1 [95% CI 1.26–81]; P = 0.029) in multivariable analysis using age, gender and the revised international prognostic score system as confounders. Transcriptional signature revealed that Favourable- and intermediate-risk patients presented enriched molecular programs related to mature myeloid progenitors, cell cycle progression, and oxidative phosphorylation, indicating that this cells differs in their origin, metabolic state, and cell cycle regulation, in comparison to the adverse-risk. Our study provides the first evidence that cellular energetics is transcriptionally deregulated in MDS CD34+ cells and establishes a new useful prognostic score based on the expression of five genes.
Highlights
Deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer, little is known about its processes in myelodysplastic syndromes (MDS)
Our rationale was to design a prognostic score interrogating the clinical and prognostic importance of transcriptionally-regulated enzymes involved in cellular energetics mechanisms of glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation, and to depict the molecular process mediated by our proposed score
To interrogate the prognostic capacity for each selected gene, we dichotomized the gene expression in high- or low-expression according to their receiving operating characteristics (ROC) curve and the C-index
Summary
Deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer, little is known about its processes in myelodysplastic syndromes (MDS). Cancer cells preferentially upregulates glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites, and, as consequence, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer c ells[6,7]. This effect, known as Warburg effect, results in reduced mitochondrial oxidative m etabolism[6,8,9], and deregulated cellular energetics is formally incorporated as an emerging hallmark of cancer[10,11]. Our rationale was to design a prognostic score interrogating the clinical and prognostic importance of transcriptionally-regulated enzymes involved in cellular energetics mechanisms of glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation, and to depict the molecular process mediated by our proposed score
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