title: Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Lucila H
authors.initials: LH
authors.lastname: Oliveira
authors.affiliation: Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Josiane L
authors.initials: JL
authors.lastname: Schiavinato
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Mariane S
authors.initials: MS
authors.lastname: Fráguas
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Lucena-Araujo
authors.affiliation: School of Ceilandia, University of Brasilia, Brasilia, Brazil.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Haddad
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Amélia G
authors.initials: AG
authors.lastname: Araújo
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Dalmazzo
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rego
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Dimas T
authors.initials: DT
authors.lastname: Covas
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zago
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Department of Genetics, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.|Center for Cell Based Therapy, Regional Blood Center, Ribeirão Preto, Brazil.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Panepucci
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003630:Daunorubicin / Q000494:pharmacology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D035683:MicroRNAs / Q000235:genetics*; D006899:Mixed Function Oxygenases; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D010544:Peroxidases; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D000097584:DNA Methyltransferase 3B; D000097423:Peroxidasin
chemical_list: D000951:Antigens, Neoplasm; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051361:Cyclin-Dependent Kinase 6; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D003630:Daunorubicin; D035683:MicroRNAs; D006899:Mixed Function Oxygenases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010544:Peroxidases; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D017472:Receptors, Interleukin-1; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C579095:MCL1 protein, human; C532045:MIRN29a microRNA, human; C462539:TET1 protein, human; C535215:PXDN protein, human; D000097423:Peroxidasin; C588001:PIK3R1 protein, human; C495911:CDK6 protein, human
keywords: DNMT; T-cell acute lymphoblastic leukemia; TET; epigenetic regulation; miR-29a