IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
capítulos de libros
Título:
The Presence of -308A TNF Allele is Associated with Clinical Parameters of Myelodysplastic Syndromes
Autor/es:
BESTACH, YESICA; FLORES, MARÍA G; SAKAMOTO, FRANCISCO; BENGIÓ, RAQUEL; LARRIPA, IRENE; BELLI, CAROLINA
Libro:
Tumor Necrosis Factor: Structure, Enzyme Regulation and Role in Health and Disease
Editorial:
Biomedical Books, Nova Science Publishers
Referencias:
Lugar: New York; Año: 2013; p. 61 - 82
Resumen:
Cytokines play important roles in the regulation of hematopoiesis, and a fine balance between the actions of stimulatory/ myelosuppressive factors is required for optimal production of cells of different hematopoietic lineages. Tumor necrosis factor-alpha (TNFa) is a multifunctional proinflammatory cytokine that has been shown to strongly inhibit hematopoiesis and has been implicated in the pathogenesis and phenotypes of Myelodysplastic Syndromes (MDS). MDS are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenia(s), and susceptibility to leukemia. The phenotypic diversity of MDS may be the consequence of a dynamic balance among the marrow microenvironment, proliferation capacity of the abnormal clone and intensity of the immune attack towards the marrow. The ineffective hematopoiesis is accompanied by an extensive apoptotic cellular death of myeloid precursors at the beginning of the disease. The bone marrow microenvironment may interact with MDS clone to create an adverse proinflammatory cytokine background associated with increased apoptotic levels. However, molecular mechanisms involved in this aberrant cytokine generation are not known. The regulatory and coding regions of cytokine genes are relatively polymorphic including a significant number of single nucleotide polymorphisms (SNPs), some of which are known to modify cytokine activity. TNF gene, located at 6p21.3, contains in its promoter region the -308G/A SNP and the -308A variant has been associated with an increased transcription and production of this cytokine. Therefore, the aim of our work was to study the -308G/A TNF SNP and to analyze whether the presence of the high producing variant is associated with clinical parameters in a cohort of 132 Argentine de novo MDS patients. We found that the A/A+G/A genotype was overrepresented 2-fold in our population (p=0.020, odds ratio-OR: 2.122) and these differences were more evident in the refractory anemia subtype (p=0.004, OR: 2.855). The presence of the high expressing -308A allele was associated with younger age (57 ± 17 vs. 65 ± 14 years, p=0.017), higher risk to present with hemoglobin levels less than 7g/dL (29% vs. 8%, p=0.002, OR: 4.688) and platelet counts less than 50000/μL (38% vs. 18%, p=0.021, OR: 2.788) at diagnosis. Also, these patients showed 3.2-fold higher risk of transfusion requirement (77% vs. 52%, p=0.012, OR: 3.205) during the follow up. In conclusion, the presence of an inherited -308A TNF, which increases the transcription level of this proinflammatory cytokine, was associated with more profound cytopenias and the necessity of transfusion requirement in our cohort of MDS patients. This immunogenetic background may influence the bone marrow microenviroment that cooperates with intrinsic defects of MDS progenitors to increase the severity of certain phenotypic features of the disease.