MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1.

// Jorge R. Contreras 1, 2 , Jayanth Kumar Palanichamy 1 , Tiffany M. Tran 1 , Thilini R. Fernando 1 , Norma I. Rodriguez-Malave 1, 2 , Neha Goswami 1 , Valerie A. Arboleda 1 , David Casero 1 , Dinesh S. Rao 1, 3, 4 1 Department of Pathology and Laboratory Medicine, UCLA 2 Cellular and Molecular Pathology Ph.D. Program, UCLA 3 Jonsson Comprehensive Cancer Center, UCLA 4 Broad Stem Cell Research Center, UCLA Correspondence to: Dinesh S. Rao, e-mail: drao@mednet.ucla.edu Keywords: microRNA, B-cell, lymphoma, leukemia, c-Myc Received: January 26, 2015      Accepted: February 24, 2015      Published: April 13, 2015 ABSTRACT miR-146a is a NF-κB induced microRNA that serves as a feedback regulator of this critical pathway. In mice, deficiency of miR-146a results in hematolymphoid cancer at advanced ages as a consequence of constitutive NF-κB activity. In this study, we queried whether the deficiency of miR-146a contributes to B-cell oncogenesis. Combining miR-146a deficiency with transgenic expression of c-Myc led to the development of highly aggressive B-cell malignancies. Mice transgenic for c-Myc and deficient for miR-146a were characterized by significantly shortened survival, increased lymph node involvement, differential involvement of the spleen and a mature B-cell phenotype. High-throughput sequencing of the tumors revealed significant dysregulation of approximately 250 genes. Amongst these, the transcription factor Egr1 was consistently upregulated in mice deficient for miR-146a. Interestingly, transcriptional targets of Egr1 were enriched in both the high-throughput dataset and in a larger set of miR-146a-deficient tumors. miR-146a overexpression led to downregulation of Egr1 and downstream targets with concomitant decrease in cell growth. Direct targeting of the human EGR1 by miR-146a was seen by luciferase assay. Together our findings illuminate a bona fide role for miR-146a in the modulation of B-cell oncogenesis and reveal the importance of understanding microRNA function in a cell- and disease-specific context.