Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type

Abstract

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL.

ETS1 phosphorylation at threonine 38 is associated with the cell of origin of diffuse large B cell lymphoma and sustains the growth of tumour cells

“…Both constructs also contained a silent mutation in the ETS1 shRNA-targeting site, allowing the shRNA-mediated silencing of the endogenous, but not of the exogenous, ETS1 in one ABC (U2932) and one GCB (Karpas-422) DLBCL cell line (Figure 3A; Figure S1). In agreement with previous reports, 5,6 the absence of ETS1 decreased the growth of both GCB and ABC DLBCL cell lines (Figure 3B). The growth impairment due to endogenous ETS1 knockdown was restored by ETS1 WT but not by Thr38Val construct (Figure 3B).…”

“…5 These two transcription factors largely co-regulate a series of genes involved in B cell signalling, differentiation and cell cycle. [5][6][7] FLI1 is expressed at a higher level in GCB than ABC DLBCL, 7 while ETS1 levels are higher in ABC than GCB DLBCL. 5,6 ETS factors family shares a unique DNA binding domain called the 'ETS' domain; in addition, several ETS proteins, including ETS1 and FLI1, contain a conserved region known as the 'Pointed' domain that is involved in protein-protein interactions.…”

“…[5][6][7] FLI1 is expressed at a higher level in GCB than ABC DLBCL, 7 while ETS1 levels are higher in ABC than GCB DLBCL. 5,6 ETS factors family shares a unique DNA binding domain called the 'ETS' domain; in addition, several ETS proteins, including ETS1 and FLI1, contain a conserved region known as the 'Pointed' domain that is involved in protein-protein interactions. In ETS1, the Pointed domain serves as a docking site for extracellular regulated kinases (ERKs), which subsequently phosphorylate the protein at threonine (Thr) 38 located upstream of the Pointed domain.…”

SASH3 is an unfavorable prognostic immune biomarker in patients with acute myeloid leukemia(AML).

“…This study explores for the rst time the mRNA expression and prognosis of SASH3 in AML, although other studies have reported a role for SASH3 in tumourigenesis, progression, metastasis, and potential therapy in several cancers [31][32][33]. Preferentially expressed in lymphoid tissues and containing SASH3 (SLY) that interact with signal transduction, it is often originally thought to be associated with proliferative diseases and cancer in humans [34]. As an important bridging protein, a growing number of studies show that SASH3 is a positive regulator of tumor immune responses [13].…”

Advances and Perspectives in the Treatment of B-Cell Malignancies

“…In connection with how genetic alterations can promote lymphomagenesis in DLBCL, Priebe et al show that ETS1 overexpression, associated with ch11q24.3 gain, contributes to the molecular pathogenesis of ABC-DLBCL regulating B-cell activation, proliferation, and resistance to apoptosis. The authors identify the Fc receptor for IgM (FCMR) as a novel ETS1 target overexpressed in ABC-DLBCL [ 14 ]. Further exploring molecular factors regulating B-NHL growth, Niu et al demonstrate that mir-26b-5p inhibits Burkitt lymphoma cell proliferation and its effect is mediated, at least in part, by binding to KPNA2 [ 15 ].…”