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- W4386948960 abstract "The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib to block B cell receptor (BCR) signaling has achieved a remarkable clinical response in several B cell malignancies including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and impacts long-term survival of these patients. Here we demonstrate that the transcription factor EGR1 is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype (ABC) DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular ATP production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL." @default.
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- W4386948960 date "2023-09-22" @default.
- W4386948960 modified "2023-09-29" @default.
- W4386948960 title "EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B cell lymphoma" @default.
- W4386948960 doi "https://doi.org/10.1182/blood.2023020142" @default.
- W4386948960 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37738652" @default.
- W4386948960 hasPublicationYear "2023" @default.
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