J Cancer 2020; 11(3):610-618. doi:10.7150/jca.34055

Research Paper

JNK/AP1 Pathway Regulates MYC Expression and BCR Signaling through Ig Enhancers in Burkitt Lymphoma Cells

Xiaoling Ding1,2*, Xiaoying Wang2*, Xueting Zhu2, Jie Zhang2, Yiqing Zhu2, Xiaoyi Shao2, Xiaorong Zhou2✉

1. Department of Gastroenterology, The Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu 226001, China.
2. Department of Immunology, Nantong University, School of Medicine, 19 Qixiu Road, Nantong, Jiangsu 226001, China.
*Xiaoying Wang and Xiaoling Ding contributed equally as first authors

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Ding X, Wang X, Zhu X, Zhang J, Zhu Y, Shao X, Zhou X. JNK/AP1 Pathway Regulates MYC Expression and BCR Signaling through Ig Enhancers in Burkitt Lymphoma Cells. J Cancer 2020; 11(3):610-618. doi:10.7150/jca.34055. Available from http://www.jcancer.org/v11p0610.htm

File import instruction

Abstract

In Burkitt lymphoma (BL), a chromosomal translocation by which the MYC gene is fused to an immunoglobulin (Ig) gene locus is frequently found. The translocated MYC gene is overexpressed, which is the major driver of BL tumorigenesis. Studies have shown that Ig enhancers are essential for MYC overexpression, but the involved mechanisms are not fully understood. In addition, the survival of BL cells relies on B-cell receptor (BCR) signaling, which is determined by the levels of Ig molecules expressed on the cell surface. However, whether MYC has any impact on Ig expression and its functional relevance in BL has not been investigated. Herein, we show that MYC upregulates Ig kappa (Igκ) expression in BL cells through two Igκ enhancers, the intronic enhancer (Ei) and the 3ʹ enhancer (E3ʹ). Mechanistically, by activating the JNK pathway, MYC induces the phosphorylation of c-Fos/c-Jun and their recruitment to AP1 binding sites in the Igκ enhancers, leading to the activation of the enhancers and subsequent Igκ upregulation. The AP1-mediated activation of the Igκ enhancers is also required for the expression of the translocated MYC gene, indicating positive feedback for the MYC overexpression in BL cells. Importantly, interrupting the JNK pathway inhibits both Igκ and MYC gene expression and suppresses BL cell proliferation. Our study not only reveals a novel mechanism underlying MYC overexpression in BL but also suggests that targeting the JNK pathway may provide a unique strategy to suppress BL tumorigenesis.

Keywords: Lymphoma, MYC, Enhancer, AP1, JNK.