EGR1 Addiction in Diffuse Large B-cell Lymphoma

Abstract

Early growth response gene (EGR1) is a transcription factor known to be a downstream effector of B-cell receptor signaling and Janus kinase 1 (JAK1) signaling in diffuse large B-cell lymphoma (DLBCL). While EGR1 is characterized as a tumor suppressor in leukemia and multiple myeloma, the role of EGR1 in lymphoma is unknown. Here we demonstrate that EGR1 is a potential oncogene that promotes cell proliferation in DLBCL. IHC analysis revealed that EGR1 expression is elevated in DLBCL compared with normal lymphoid tissues and the level of EGR1 expression is higher in activated B cell–like subtype (ABC) than germinal center B cell–like subtype (GCB). EGR1 expression is required for the survival and proliferation of DLBCL cells. Genomic analyses demonstrated that EGR1 upregulates expression of MYC and E2F pathway genes through the CBP/p300/H3K27ac/BRD4 axis while repressing expression of the type I IFN pathway genes by interaction with the corepressor NAB2. Genetic and pharmacologic inhibition of EGR1 synergizes with the BRD4 inhibitor JQ1 or the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL both in cell cultures and xenograft mouse models. Therefore, targeting oncogenic EGR1 signaling represents a potential new targeted therapeutic strategy in DLBCL, especially for the more aggressive ABC DLBCL. Implications: The study characterizes EGR1 as a potential oncogene that promotes cell proliferation and defines EGR1 as a new molecular target in DLBCL, the most common non-Hodgkin lymphoma.

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

“…This concentration of doxycycline was not toxic for lymphoma cells, and uninduced cells served as controls as described in our recent studies. 25 , 26 …”

Enhancer-driven gene regulatory networks inference from single-cell RNA-seq and ATAC-seq data

“…SPI1 and TCF12 are essential for B cell functionality, while ZFP42 (REX1) is connected to lymph node oncogenesis [ 58–60 , 67 , 68 ]. Tumor B cells shared similarities with Tumor B proliferation cells, with the addition of an EGR1 eRegulon, a gene implicated in B-cell lymphoma signaling pathways [ 69 ]. STREAM's analysis reveals intricate TF–enhancer–gene dynamics, offering insights into the molecular underpinnings of Tumor B cell biology.…”

Enhancer-driven gene regulatory networks inference from single-cell RNA-seq and ATAC-seq data

“…The major difference between eRegulons specific to Tumor B proliferation and Tumor B cells was that an EGR1 (Early growth response gene) eRegulon was discovered in Tumor B cells. EGR1 is a TF known to be a downstream effector of B-cell receptor signaling and Janus kinase 1 signaling in B-cell lymphoma (74). In sum, STREAM could discover trustworthy TF-enhancer-gene relations that can explain two Tumor B cell types.…”