A network including PU.1, Vav1 and miR-142-3p sustains ATRA-induced differentiation of acute promyelocytic leukemia cells - a short report

• Published in: Cellular oncology (Dordrecht) Vol. 39; no. 5; pp. 483 - 489
• Main Authors: Grassilli, Silvia, Nika, Ervin, Lambertini, Elisabetta, Brugnoli, Federica, Piva, Roberta, Capitani, Silvano, Bertagnolo, Valeria
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.10.2016; Springer Nature B.V
• Subjects: Acute promyeloid leukemia; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Differentiation - drug effects; Cell Line, Tumor; Chromatin Immunoprecipitation; Gene Expression Regulation, Leukemic - genetics; Gene Knockdown Techniques; Hematological diseases; Humans; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - metabolism; MicroRNAs - biosynthesis; MicroRNAs - genetics; miRNA; Myeloid leukemia; Oncology; Pathology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-vav - metabolism; PU.1 protein; Real-Time Polymerase Chain Reaction; Retinoic acid; siRNA; Therapeutic applications; Trans-Activators - metabolism; Tretinoin - pharmacology; Acute promyelocytic leukemia; miR-142-3p; ATRA; PU.1; Vav1
• ISSN: 2211-3428; 2211-3436
• DOI: 10.1007/s13402-016-0292-6

Purpose 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.