Molecular-Based Score inspired on metabolic signature improves prognostic stratification for myelodysplastic syndrome

Author(s)

Coelho-Silva, Juan L. ^{[1, 2]} ; Silveira, Douglas R. A. ^{[3, 4]} ; Pereira-Martins, Diego A. ^{[5, 2]} ; Rojas, Cesar A. O. ^[2] ; Lucena-Araujo, Antonio R. ^[6] ; Rego, Eduardo M. ^{[2, 3]} ; Machado-Neto, Joao A. ^[7] ; Bendit, Israel ^[3] ; Rocha, Vanderson ^[3] ; Traina, Fabiola ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Ribeirao Preto, SP - Brazil

^[2] Sao Paulo Res Fdn, Ctr Cell Based Therapy, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Med, Hematol Div, LIM31, Sao Paulo, SP - Brazil

^[4] AC Camargo Canc Ctr, Dept Haematol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto, SP - Brazil

^[6] Univ Fed Pernambuco, Dept Genet, Recife, PE - Brazil

^[7] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 11, n. 1 JAN 18 2021.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model
• Grantee: Diego Antonio Pereira Martins
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23191-4 - Investigation of IRS2 role on the pathogenesis of myeloproliferative neoplasms JAK2V617F using murine models
• Grantee: Juan Luiz Coelho da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/19864-6 - Investigation of IRS1 and IRS2 function in normal hematopoiesis and myelodysplastic syndrome using murine models and human hematopoietic stem cells
• Grantee: Fabíola Traina
• Support Opportunities: Regular Research Grants