MYC Protein Dysregulation is Driven by BCR-PI3K Signaling in Diffuse Large B-cell Lymphoma

Abstract

Introduction

MYC overexpression is a common feature of diffuse large B-cell lymphoma (DLBCL) and is associated with poor prognosis in patients with this neoplasm. The underlying mechanisms of MYC dysregulation, however, have not been fully understood.

Materials and methods

We immunohistochemically evaluated the correlation between BCR-PI3K pathway activity and MYC protein level in 108 cases of de novo DLBCL, twenty five of which featured loss of B-cell receptor (BCR-negative), and investigated the effects of BCR-PI3K signaling on MYC protein level and phosphorylation in DLBCL cell lines.

Results

The expression level of pSYK and pAKT correlated with MYC protein in BCR-positive DLBCL. MYC protein expression was significantly lower in BCR-negative tumor tissues compared to BCR-positive ones. Upon BCR stimulation, the BCR-positive cell lines demonstrated active BCR-PI3K signaling and decreased MYC phosphorylation at T58 site (pT58-MYC), leading to increased overall level of MYC. Conversely, inhibition of BCR-PI3K signaling increased MYC phosphorylation and thus resulting in a decreased level of total MYC proteins. No effects were observed in the BCR-negative cell lines.

Conclusions

Overexpression of MYC in DLBCL can be driven by BCR-PI3K signaling pathway via dephosphorylation at T58, and BCR inhibitors may exert their functions via down-regulating of MYC protein.

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