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Int J Mol Sci ; 24(6)2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36982699

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.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , NF-kappa B , Humans , NF-kappa B/genetics , NF-kappa B/metabolism , Galectin 3/metabolism , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Mutation , Gene Expression Profiling , Basic-Leucine Zipper Transcription Factors/genetics , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Adaptor Proteins, Signal Transducing/metabolism
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