Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma
The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib has achieved a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and impacts long-term survival of MCL patients. Here we demonstrate that DNMT3A is involved in ibrutinib resistance. We found that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses revealed that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS).  Targeting DNMT3A by a low dose of decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-medited metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL. Overall design: To generate DNMT3A KO clones, Z138 cell line was transduced with CAS9-RFP and sgDNMT3A (2 guides) whose expression can be induced by doxycycline. Uninduced clones are preserved in different vials. For every experiment, uninduced cells were freshly thawn to use. For RNA-sequencing, 3 biological replicates were performed, that means cells frozen in different vials were  induced on 3 different day.  For each biological replicate, 2 technical duplicates were performed. Their total RNA are then pooled for analysis. For ChIP-seq, Z138 WT was used and DNMT3A KO in Z138 clone 7 was used as negative control.