The c-Myc/miR17-92/PTEN Axis Tunes PI3K Activity to Control Expression of Recombination Activating Genes in Early B Cell Development.

David Benhamou,Doron Melamed,Eli Benchetrit,Andrew Getahun,Verena Labi,John C Cambier,Klaus Rajewsky,Reem Dowery

doi:10.3389/fimmu.2018.02715

Abstract

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. Studies using 38c-13 B lymphoma cells, where RAGs are constitutively expressed, suggest that this regulatory effect is mediated post-translationally through Foxo1.

Highlights

The development of B lymphocytes in the bone marrow (BM) is a highly regulated process guided by the successive attempts to recombine immunoglobulin (Ig) genes and to assemble the B cell antigen receptor (BCR)
As phosphoinositide 3-kinase (PI3K) signals are necessary to turn off Recombination activating gene (RAG) [17, 18, 20], we tested whether the c-Myc/miR17-92/phosphatase and tensin homolog (PTEN) functions to tune PI3K activity to control RAG expression during B cell development
Despite of this mild pro-to-pre B cell block we found no significant differences in splenic B cells. These findings suggest that intrinsic deletion of miR17-92 in proB cells impairs the regulatory activity of the c-Myc/miR17-92/PTEN axis to result in enhanced RAG expression and a partial pro-to-preB block

Summary

Introduction

The development of B lymphocytes in the bone marrow (BM) is a highly regulated process guided by the successive attempts to recombine immunoglobulin (Ig) genes and to assemble the B cell antigen receptor (BCR). Recombination activating gene (RAG)-1 and RAG-2 are key enzymes in this process and their expression is tightly regulated by signals generated by the antigen receptor to promote developmental progression through negative and positive selection check-points. PI3K signals that are too high, such as in PTEN-ablated B cells, suppress RAG expression and impose a severe developmental block at the proB stage [22]. These studies show that generation of appropriate PI3K activity is crucial to control RAG levels, allowing for proper developmental progression. The exact physiological mechanism and/or biochemical circuit which tunes PI3K activity to control RAG expression at these early stages of B cell development are unknown

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Conclusion