Repression of TCF3/E2A contributes to Hodgkin lymphomagenesis.

Alexey Ushmorov,Hanfeng Guan,Thomas Wirth,Linka Xie

doi:10.18632/oncotarget.9210

Abstract

Although Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) derived from germinal or post germinal B cells, they have lost the B cell phenotype in the process of lymphomagenesis. The phenomenon can be at least partially explained by repression of B-cell-specific transcription factors including TCF3, early B-cell factor 1 (EBF1), SPI1/PU.1, and FOXO1, which are down-regulated by genetic and epigenetic mechanisms. The unique phenotype has been suspected to be advantageous for survival of HRS cells. Ectopic expression of some of these transcription factors (EBF1, PU.1, FOXO1) indeed impaired survival of cHL cells. Here we show that forced expression of TCF3 causes cell death and cell cycle arrest in cHL cell lines. Mechanistically, TCF3 overexpression modulated expression of multiple pro-apoptotic genes including BIK, APAF1, FASLG, BOK, and TNFRSF10A/DR4. We conclude that TCF3 inactivation contributes not only to extinguishing of B cell phenotype but also to cHL oncogenesis.

Highlights

Classical Hodgkin lymphoma is characterized by the presence of mononucleated Hodgkin cells and multinucleated Reed-Sternberg cells (HRS) surrounded by the overwhelming host cells of “inflammatory infiltrate”
Since endogenous TCF3 proteins are bona fide inactivated by ID2 and MSC in classical Hodgkin lymphoma (cHL), we overexpressed E47, a TCF3 transcription variant, in KM-H2 and SUPHD1 cell lines using doxycycline (DOX)-inducible vector pRTS containing green fluorescent protein (GFP) as a fluorescent marker
We found that expression of BCL2-interacting killer (BIK) in most NHL cell lines was higher than in normal CD19+ B cells. cHL cell lines showed a virtual absence of BIK expression (Figure 4A), which is in agreement with a previous study [14]

Summary

Introduction

Classical Hodgkin lymphoma (cHL) is characterized by the presence of mononucleated Hodgkin cells and multinucleated Reed-Sternberg cells (HRS) surrounded by the overwhelming host cells of “inflammatory infiltrate”. Multiple pathways that are critical for evading apoptosis and for promotion of cell growth are constitutively activated in HRS cells. They include NF-κB, the Jak-Stat, PI3K-Akt, Erk, AP1, and NOTCH pathways [1]. HRS cells have lost their B cell identity, and acquired expression of markers of other lineages, especially that of T lymphocytes like NOTCH1and GATA3 [1]. Repression of the transcription factors regulating maintenance of B cell program including POU2F2, POU2AF1, SPI1/ PU., EBF1, and FOXO1 by genetic and epigenetic mechanisms was shown to be responsible for the loss of specific B-cell markers in cHL [1, 2]. The antitumor effect of the TCF3 is accompanied by induction of proapoptotic and antiproliferative genes like BIK, APAF1, FASLG, BOK, and TNFRSF10A/DR4, and p21

Methods

Results

Conclusion