RESUMEN
This study evaluated the loss and expression level of miRNAs 14q32 clusters in acute lymphoblastic leukemia (ALL) patients with cryptic deletions at 14q32 chromosomal band to investigate their involvement in this disease. We demonstrate that a subset of ALL cases bearing 14q32 LOH showed a down-regulation of miRNA 14q32 clusters, which is directly linked to the submicroscopic chromosomal deletion. As a consequence of miRNAs deregulation we reported an inverse correlation with the expression of their target BCL11a, a transcription factor involved in lymphoid differentiation. These results suggest that 14q32/miRNA clusters LOH may be another mechanism involved in lymphoid B cell transformation and differentiation and therefore, could be used as a diagnostic marker and therapeutic target in subsets of ALL.
Asunto(s)
Proteínas Portadoras/biosíntesis , Cromosomas Humanos Par 14/genética , Regulación Leucémica de la Expresión Génica/genética , Pérdida de Heterocigocidad , MicroARNs/genética , Proteínas de Neoplasias/biosíntesis , Proteínas Nucleares/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , ARN Neoplásico/genética , Eliminación de Secuencia , Adolescente , Adulto , Anciano , Proteínas Portadoras/genética , Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Niño , Cromosomas Humanos Par 14/ultraestructura , Femenino , Humanos , Masculino , MicroARNs/biosíntesis , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , ARN Neoplásico/biosíntesis , Proteínas Represoras , Regulación hacia Arriba , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) the most common acute leukemia in adults is characterized by various cytogenetic and molecular abnormalities. However, the genetic etiology of the disease is not yet fully understood. MicroRNAs (miRNA) are small noncoding RNAs which regulate the expression of target mRNAs both at transcriptional and translational level. In recent years, miRNAs have been identified as a novel mechanism in gene regulation, which show variable expression during myeloid differentiation. We studied miRNA expression of leukemic blasts of 29 cases of newly diagnosed and genetically defined AML using quantitative reverse transcription polymerase chain reaction (RT-PCR) for 365 human miRNA. We showed that miRNA expression profiling reveals distinctive miRNA signatures that correlate with cytogenetic and molecular subtypes of AML. Specific miRNAs with consolidated role on cell proliferation and differentiation such as miR-155, miR-221, let-7, miR-126 and miR-196b appear to be associated with particular subtypes. We observed a significant differentially expressed miRNA profile that characterizes two subgroups of AML with different mechanism of leukemogenesis: core binding factor (CBF) and cytogenetically normal AML with mutations in the genes of NPM1 and FLT3-ITD. We demonstrated, for the first time, the inverse correlation of expression levels between miRNA and their targets in specific AML genetic groups. We suggest that miRNA deregulation may act as complementary hit in the multisteps mechanism of leukemogenesis offering new therapeutic strategies.