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Front. Immunol. | doi: 10.3389/fimmu.2018.02715

The c-Myc/miR17-92/PTEN axis tunes PI3K activity to control expression of recombination activating genes in early B cell development

David Benhamou1, Verena Labi2,  Andrew Getahun3, Eli Benchetrit1, Reem Dowery1,  Klaus Rajewsky4,  John Cambier3 and  Doron Melamed1*
  • 1Technion – Israel Institute of Technology, Israel
  • 2Innsbruck Medical University, Austria
  • 3School of Medicine, University of Colorado, United States
  • 4Max Delbrück Center for Molecular Medicine, Germany

Appropriate PI3K signals generated by the antigen receptor are essential to promote B cell development. Regulation of recombination activating gene (RAG)-1 and RAG-2 expression is one key process that is mediated by PI3K to ensure developmental progression and selection. When PI3K signals are too high or too low, expression of RAGs does not turn off and B cell development is impaired or blocked. Yet, the mechanism which tunes PI3K activity to control RAG expression during B cell development in the bone marrow is unknown. Recently we showed that a c-Myc/miR17-92/PTEN axis regulates PI3K activity for positive and negative selection of immature B cells. Here we show that the c-Myc/miR17-92/PTEN axis tunes PI3K activity to control the expression of RAGs in proB cells. Using different genetically engineered mouse models we show that impaired function of the c-Myc/miR17-92/PTEN axis alters the PI3K/Akt/Foxo1 pathway to result in dis-regulated expression of RAG and a block in B cell development. Using 38c-13 B lymphoma cells, where RAGs are constitutively expressed, we show that this regulatory effect is mediated post-translationally through Foxo1.

Keywords: B cell development, Recombination Activating Gene (RAG), PI3K - AKT pathway, microRNA, PTEN (phosphatase and tensin homolog)

Received: 16 Aug 2018; Accepted: 05 Nov 2018.

Edited by:

Amy L. Kenter, University of Illinois at Chicago, United States

Reviewed by:

Paulo Vieira, Institut Pasteur, France
Rachel M. Gerstein, University of Massachusetts Medical School, United States  

Copyright: © 2018 Benhamou, Labi, Getahun, Benchetrit, Dowery, Rajewsky, Cambier and Melamed. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Doron Melamed, Technion – Israel Institute of Technology, Haifa, Israel, melamedd@technion.ac.il