Physiological levels of the PTEN-PI3K-AKT axis activity are required for maintenance of Burkitt lymphoma

Franziska Gehringer,Alexey Ushmorov,Peter Möller,Thomas Wirth,Stephanie Ellen Weissinger

doi:10.1038/s41375-019-0628-0

Abstract

In addition to oncogenic MYC translocations, Burkitt lymphoma (BL) depends on the germinal centre (GC) dark zone (DZ) B cell survival and proliferation programme, which is characterized by relatively low PI3K-AKT activity. Paradoxically, PI3K-AKT activation facilitates MYC-driven lymphomagenesis in mice, and it has been proposed that PI3K-AKT activation is essential for BL. Here we show that the PI3K-AKT activity in primary BLs and BL cell lines does not exceed that of human non-neoplastic tonsillar GC DZ B cells. BLs were not sensitive to AKT1 knockdown, which induced massive cell death in pAKThigh DLBCL cell lines. Likewise, BL cell lines show low sensitivity to pan-AKT inhibitors. Moreover, hyper-activation of the PI3K-AKT pathway by overexpression of a constitutively active version of AKT (myrAKT) or knockdown of PTEN repressed the growth of BL cell lines. This was associated with increased AKT phosphorylation, NF-κB activation, and downregulation of DZ genes including the proto-oncogene MYB and the DZ marker CXCR4. In contrast to GCB-DLBCL, PTEN overexpression was tolerated by BL cell lines. We conclude that the molecular mechanisms instrumental to guarantee the survival of normal DZ B cells, including the tight regulation of the PTEN-PI3K-AKT axis, also operate in the survival/proliferation of BL.

Highlights

Burkitt lymphoma (BL) is the most common aggressive type of B cell lymphoma in children and occurs in adults [1]
PI3K-AKT activity of BL cell lines does not exceed that of germinal centre (GC) dark zone (DZ) B cells and is much lower than of PTEN-negative GCB-DLBCL cell lines
PAKTT308 and pAKTS473 signals were detected in all pAKThigh GCBDLBCL cell lines (Fig. 1a) but in none of BLs. pAKTT308 and pAKTS473 signals were detected in BL cell lines only at longer exposure time, when the signals of pAKThigh GCB

Summary

Introduction

Burkitt lymphoma (BL) is the most common aggressive type of B cell lymphoma in children and occurs in adults [1]. BL originates from germinal centre (GC) B cells [2], and is characterized by translocation of the protooncogene MYC under the control of immunoglobulin heavy or light chain loci [3]. The GC is divided in a dark zone (DZ) and a light zone (LZ). These authors contributed : Thomas Wirth, Alexey Ushmorov

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Conclusion