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

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-kappa B 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 MyD88(L265P) activates NF-kappa B signaling and upregulates genes that might contribute to lymphomagenesis, including CD44, LGALS3 (coding Galectin-3), NFKBIZ (coding IkB(sic)), 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 MyD88(L265P) oncogenic signaling that might be involved in cellular transformation and provide novel therapeutical targets.

Automated summary

During innate immune responses, the adaptor protein MyD88 integrates stimuli from toll-like receptors and IL-1R family, playing a critical role in cellular outcomes. Somatic mutations in MyD88 can trigger independent oncogenic signaling in B cells, leading to the development of B-cell malignancies. Through transcriptomic analysis, this study identified genes upregulated by the oncogenic MyD88(L265P) mutation and revealed a potential role of CD44 as a marker for ABC subtype of DLBCL with prognostic implications. These findings shed light on the downstream effects of MyD88(L265P) signaling and provide novel therapeutic targets.