title: A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report.
abstract: OBJECTIVE
  Reduced expression of miR-142-3p has been found to be associated with the development of various subtypes of myeloid leukemia, including acute promyelocytic leukemia (APL). In APL-derived cells, miR-142-3p expression can be restored by all-trans retinoic acid (ATRA), which induces the completion of their maturation program. Here, we aimed to assess whether PU.1, essential for ATRA-induced gene transcription, regulates the expression of miR-142-3p in APL-derived cells and, based on the established cooperation between PU.1 and Vav1 in modulating gene expression, to evaluate the role of Vav1 in restoring the expression of miR-142-3p.
  
  
  METHODS
  ATRA-induced increases in PU.1 and Vav1 expression in APL-derived NB4 cells were counteracted with specific siRNAs, and the expression of miR-142-3p was measured by quantitative real-time PCR (qRT-PCR). The recruitment of PU.1 and/or Vav1 to the regulatory region of miR-142 was assessed by quantitative chromatin immunoprecipitation (Q-ChIP). Synthetic inhibitors or mimics for miR-142-3p were used to assess whether this miRNA plays a role in regulating the expression of PU.1 and/or Vav1.
  
  
  RESULTS
  We found that the expression of miR-142-3p in differentiating APL-derived NB4 cells is dependent on PU.1, and that Vav1 is essential for the recruitment of this transcription factor to its cis-binding element on the miR-142 promoter. In addition, we found that in ATRA-treated NB4 cells miR-142-3p sustains agonist-induced increases in both PU.1 and Vav1.
  
  
  CONCLUSIONS
  Our results suggest the existence of a Vav1/PU.1/miR-142-3p network that supports ATRA-induced differentiation in APL-derived cells. Since selective regulation of miRNAs may play a role in the future treatment of hematopoietic malignancies, our results may provide a basis for the development of new therapeutic strategies to restore the expression of miR-142-3p.
authors.affiliation: Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Grassilli
authors.affiliation: Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Ervin
authors.initials: E
authors.lastname: Nika
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lambertini
authors.affiliation: Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Brugnoli
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Piva
authors.affiliation: Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.|LTTA, University of Ferrara, 44121, Ferrara, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.affiliation: Section of Anatomy and Histology, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy. bgv@unife.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bertagnolo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C555159:MIRN142 microRNA, human; C496618:VAV1 protein, human
keywords: ATRA; Acute promyelocytic leukemia; PU.1; Vav1; miR-142-3p