DNMT3A-Mediated Oxidative Phosphorylation and Ibrutinib Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma, is incurable with current treatment modalities. Targeting Bruton tyrosine kinase (BTK) in the early B cell receptor signaling pathway by ibrutinib has shown remarkable anti-tumor activity, with the overall response rate of 68% in relapsed/refractory MCL patients. However, almost all the responders relapsed after ibrutinib treatment, with the 1-year survival rate of 22%. To overcome primary and acquired resistance to ibrutinib, novel treatment strategies are urgently needed.

The presence of a relapse-specific C481S mutation in BTK associated with acquired ibrutinib resistance has been frequently identified in chronic lymphocytic leukemia but is rare in clinical MCL specimens based on sequencing results. Thissuggests that non-genetic aberrations likely play a role in ibrutinib resistance. The recent emergence of mitochondrial oxidative phosphorylation (OXPHOS) as a driver of ibrutinib resistance warrants the necessity to identify the components that govern OXPHOS in MCL. This study identifies the de novo DNA methyltransferase 3A (DNMT3A) as a mediator of mitochondrial biogenesis and OXPHOS in MCL. Using multiomics and functional approaches, we found that DNMT3A is required and sufficient to confers ibrutinib resistance in MCL. We show that DNMT3A promotes MCL growth by enhancing mitochondrial biogenesis, mitochondrial functions and OXPHOS. These effects are mediated by its interaction with MEF2B, a transcriptional activator of MYC, to enhance MYC-mediated transcription of genes involved in mitochondrial biogenesis. More importantly, the level of DNMT3A protein increases after ibrutinib treatment in primary MCL, which is consistent with a previous finding that the expression of DNMT3A was higher in ibrutinib-resistant than in ibrutinib-sensitive MCL patients. We demonstrate that DNMT3A knockout sensitizes ibrutinib-resistant cells to ibrutinib treatment. Conversely, the overexpression of DNMT3A cDNA de-sensitizes ibrutinib-sensitive cell lines. Interestingly, the overexpression of a catalytically dead DNMT3A confers resistance to ibrutinib in ibrutinib-sensitive cell lines, suggesting that DNMT3A-mediated ibrutinib resistance is independent of its enzymatic activity. Finally, we demonstrate that targeting DNMT3A by a low dose of decitabine, which induces the degradation of DNMT3A protein, synergizes with IM156, an inhibitor of mitochondrial complex I and currently in phase I clinical trial, in killing ibrutinib-resistant cell lines and primary MCL cells. Currently, we are testing this synergistic effect using patient-derived xenograft mouse models. Therefore, our study reveals a novel noncatalytic function of DNMT3A and suggests that DNMT3A is a potential biomarker and molecular target in treating MCL (Figure 1).

No relevant conflicts of interest to declare.