Down-regulated expression of hsa-miR-181c in Fanconi anemia patients: implications in TNF alpha regulation and proliferation of hematopoietic progenitor cells
Por:
Rio, P, Agirre, X, Garate, L, Banos, R, Alvarez, L, San Jose-Eneriz, E, Badell, I, Casado, JA, Garin, M, Prosper, F, Bueren, JA
Publicada:
29 mar 2012
Resumen:
Fanconi anemia (FA) is an inherited genetic disorder associated with BM failure and cancer predisposition. In the present study, we sought to elucidate the role of microRNAs (miRNAs) in the hematopoietic defects observed in FA patients. Initial studies showed that 3 miRNAs, hsa-miR-133a, hsa-miR-135b, and hsa-miR181c, were significantly down-regulated in lymphoblastoid cell lines and fresh peripheral blood cells from FA patients. In vitro studies with cells expressing the luciferase reporter fused to the TNF alpha 3'-untranslated region confirmed in silico predictions suggesting an interaction between hsa-miR-181c and TNF alpha mRNA. These observations were consistent with the down-regulated expression of TNF alpha mediated by hsa-miR-181c in cells from healthy donors and cells from FA patients. Because of the relevance of TNF alpha in the hematopoietic defects of FA patients, in the present study, we transfected BM cells from FA patients with hsa-miR-181c to evaluate the impact of this miRNA on their clonogenic potential. hsa-miR-181c markedly increased the number and size of the myeloid and erythroid colonies generated by BM cells from FA patients. Our results offer new clues toward understanding the biologic basis of BM failure in FA patients and open new possibilities for the treatment of the hematologic dysfunction in FA patients based on miRNA regulation. (Blood. 2012;119(13):3042-3049)
Filiaciones:
Rio, P:
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
Agirre, X:
Univ Navarra, Fdn Invest Med Aplicada, E-31080 Pamplona, Spain
Univ Navarra Clin, Dept Hematol, Pamplona, Spain
Garate, L:
Univ Navarra, Fdn Invest Med Aplicada, E-31080 Pamplona, Spain
Univ Navarra Clin, Dept Hematol, Pamplona, Spain
Banos, R:
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
Alvarez, L:
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
San Jose-Eneriz, E:
Univ Navarra, Fdn Invest Med Aplicada, E-31080 Pamplona, Spain
Univ Navarra Clin, Dept Hematol, Pamplona, Spain
Badell, I:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Casado, JA:
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
Garin, M:
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
Prosper, F:
Univ Navarra, Fdn Invest Med Aplicada, E-31080 Pamplona, Spain
Univ Navarra Clin, Dept Hematol, Pamplona, Spain
Bueren, JA:
CIEMAT CIBERER, Ctr Invest Energet Medioambientales & Tecnol, Hematopoiesis & Gene Therapy Div, Madrid 28040, Spain
Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain
|