RESUMEN

Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease.

Asunto(s)

Metilación de ADN/genética , Epigénesis Genética/genética , Regulación Leucémica de la Expresión Génica/genética , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Antígenos de Neoplasias/biosíntesis , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Fosfatidilinositol 3-Quinasa Clase Ia , Quinasa 6 Dependiente de la Ciclina/biosíntesis , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Proteínas de Unión al ADN/biosíntesis , Daunorrubicina/farmacología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/genética , Humanos , Células Jurkat , Oxigenasas de Función Mixta , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/biosíntesis , Análisis de Secuencia por Matrices de Oligonucleótidos , Peroxidasas , Fosfatidilinositol 3-Quinasas/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Receptores de Interleucina-1/biosíntesis , ADN Metiltransferasa 3B