Down-regulated expression of hsa-miR-181c in Fanconi anemia patients: implications in TNFα regulation and proliferation of hematopoietic progenitor cells.
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-miR-181c, 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 TNFα 3'-untranslated region confirmed in silico predictions suggesting an interaction between hsa-miR-181c and TNFα mRNA. These observations were consistent with the down-regulated expression of TNFα mediated by hsa-miR-181c in cells from healthy donors and cells from FA patients. Because of the relevance of TNFα 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.
Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
Paula
P
Río
Xabier
X
Agirre
Leire
L
Garate
Rocío
R
Baños
Lara
L
Álvarez
Edurne
E
San José-Enériz
Isabel
I
Badell
José A
JA
Casado
Marina
M
Garín
Felipe
F
Prósper
Juan A
JA
Bueren
D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha