Abstract 3041: A tumor-suppressive role of the IL-21R/Jak/STAT3 pathway in the germinal center B cell subtype of diffuse large B cell lymphomas.
Authors: Ye B. Hilda , Bi Enguang , Yu J. Jessica , Mai Yun , Ding B. Belinda , Yu Yiting , Verma Amit , Shaknovich Rita , Chan Wing C. 
Published: August 2014

Diffuse large B cell lymphoma (DLBCL) is the most common type of B cell malignancy in the adult population. Based on their patterns of gene expression, DLBCLs can be divided into two major subgroups: the germinal center (GC) B cell like (GCB-DLBCL) and the activated B cell like (ABC-DLBCL) cases. Current studies suggest that the cell-of-origin for both subgroups is a normal GC B cell. The difference lies in the degree of maturation. While the GCB variant corresponds to the GC centroblasts that abundantly express BCL6 with no NF-kappaB activation, the ABC variant phenotypically resembles activated GC centrocytes and plasma cell precursors that have received activating signals (e.g. IL-21 and CD40L) from follicular T helper (Tfh) cells and thus contain activated STAT3 and NF-kappaB due to mutations in a high percentage of cases. Although it is commonly accepted that pathogenesis of B cell lymphomas such as DLBCL is intimately linked to impaired B cell differentiation, a direct examination of this concept has not been made for GCB-DLBCL. In a previous study, we showed that the IL-21R/Jak/Stat3 signaling pathway plays a critical role in post-GC plasma cell differentiation, while concurrent signals transduced through the CD40/NF-kappaB axis potentiate the activity of Jak/Stat3 through two distinct mechanisms. In the current study, we report that IL-21-triggered Stat3 activation is often defective in GCB-DLBCL cell lines. Impaired STAT3 activation results in failure to commit to the plasma cell fate as evidenced by lack of Blimp-1 induction. The IL-21 insensitive cell lines either have very low levels of IL-21R or lack the Jak3 protein. Aberrant expression of the components of the IL-21R/Jak/STAT3 signaling pathway can also be detected in subsets of primary GCB-DLBCL samples. Lentivirus mediated reconstitution of IL-21R and Jak3 in the defective cell lines restored IL-21 responsiveness and induced a delayed cell death phenotype, indicating that low level expression of a single signaling molecule is responsible for the IL-21R signaling defect in a given cell line. We have sequenced the coding regions of the IL21R, Jak3 and STAT3 genes in 3 cell lines, but did not find any mutations. Subsequent analyses showed that the IL-21R abnormality is a transcriptional defect associated with Sp1 expression changes, while silencing of the Jak3 gene is caused by promoter methylation. Collectively, our results suggest that in GCB-DLBCL, the IL-21R/Jak/STAT3 pathway plays a novel, tumor suppressive role, and its epigenetic inactivation may promote lymphoma development by blocking terminal B cell differentiation.

Citation Format: B. Hilda Ye, Enguang Bi, J. Jessica Yu, Yun Mai, B. Belinda Ding, Yiting Yu, Amit Verma, Rita Shaknovich, Wing C. Chan. A tumor-suppressive role of the IL-21R/Jak/STAT3 pathway in the germinal center B cell subtype of diffuse large B cell lymphomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3041. doi:10.1158/1538-7445.AM2013-3041