Transcriptome Analysis of Diffuse Large B-Cell Lymphoma Cells Inducibly Expressing MyD88 L265P Mutation Identifies Upregulated CD44, LGALS3, NFKBIZ, and BATF as Downstream Targets of Oncogenic NF-κB Signaling

Abstract

During innate immune responses, myeloid differentiation primary response 88 (MyD88) functions as a critical signaling adaptor protein integrating stimuli from toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family and translates them into specific cellular outcomes. In B cells, somatic mutations in MyD88 trigger oncogenic NF-κB signaling independent of receptor stimulation, which leads to the development of B-cell malignancies. However, the exact molecular mechanisms and downstream signaling targets remain unresolved. We established an inducible system to introduce MyD88 to lymphoma cell lines and performed transcriptomic analysis (RNA-seq) to identify genes differentially expressed by MyD88 bearing the L265P oncogenic mutation. We show that MyD88L265P activates NF-κB signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkBƺ), and BATF. Moreover, we demonstrate that CD44 can serve as a marker of the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and that CD44 expression is correlated with overall survival in DLBCL patients. Our results shed new light on the downstream outcomes of MyD88L265P oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.

BATF controls IFN I production via DC-SCRIPT in plasmacytoid dendritic cells

“…IFNAR signals, however, may only contribute to Batf expression in pDCs in the presence of a second signal induced by TLR9 activation in pDCs. Previous studies have demonstrated the requirement of the TLR4/MyD88-NFκB axis for induction of BATF expression in a B cell line 35, 36, 37 . In addition, also cytokines such as IL-10, LIF, IL-6, IL-7, and IL-21, which signal through Jak/Stat signaling pathways, have been shown to induce BATF in various cell types 38, 39, 40 .…”

“…In addition, also cytokines such as IL-10, LIF, IL-6, IL-7, and IL-21, which signal through Jak/Stat signaling pathways, have been shown to induce BATF in various cell types 38, 39, 40 . Strikingly, blocking the NFκB activity by specifically inhibiting TAK1 or Stat3 and Stat6 functions abrogated Myd88 mediated BATF expression in Large B-cell Lymphoma cells 37 or IL-7-induced BATF expression in innate lymphoid cell (ILC) progenitors 16 , respectively. In addition, Notch signaling has also been associated with BATF expression in B cells 41 .…”

Identification of prognostic biomarkers of smoking-related lung cancer

“…The GEO database and TCGA database are popular and widely used biomedical information repositories, covering nearly all genomics, transcriptomics, proteomics, epigenetics, and other omics data related to organs, tissues, and cells. They are the largest and most comprehensive tumor gene information databases globally ( 28 , 29 ) and thus have greatly improved the early diagnosis and prevention of cancer by providing support for the in-depth understanding of cancer’s pathogenic factors and mechanisms from molecular and genetic perspectives ( 30 , 31 ). In recent years, researchers have integrated and analyzed data to uncover the pathogenic mechanisms of related tumors.…”

NFKBIZ regulates NFκB signaling pathway to mediate tumorigenesis and metastasis of hepatocellular carcinoma by direct interaction with TRIM16

“…NFKBIZ played a bidirectional role in the progression of divergent tumors. Research on diffuse large B-cell lymphoblastoma (DLBCL) proposed that approximately 40% of primary testicular DLBCL (PT-DLBCL) patients were accompanied by NFKBIZ somatic cell mutations, and the abnormal expression of NFKBIZ promoted PT-DLBCL advancement [ 7 , 8 ]. Notably, the mutation rate of NFKBIZ was higher in intestinal epithelial cells in the context of ulcerative colitis, but lower in colitis-led tumor cells, suggesting that intestinal epithelial cells may resist tumor transformation through selective NFKBIZ mutation [ 9 ].…”