Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Bruton tyrosine kinase (BTK) inhibitors like ibrutinib are effective in mantle cell lymphoma (MCL).
• Acquired resistance to ibrutinib significantly impacts long-term survival in MCL patients.
• Mechanisms underlying ibrutinib resistance in MCL require further elucidation.

Purpose of the Study:

• To investigate the role of DNA methyltransferase 3A (DNMT3A) in mediating ibrutinib resistance in MCL.
• To explore the therapeutic potential of targeting DNMT3A in overcoming ibrutinib resistance.

Main Methods:

• Analysis of DNMT3A expression in ibrutinib-treated MCL cells.
• Genetic and pharmacological inhibition of DNMT3A.
• Investigation of DNMT3A's interaction with transcription factors MEF2B and MYC.
• Assessment of metabolic reprogramming to oxidative phosphorylation (OXPHOS).
• In vitro and in vivo efficacy studies using decitabine in patient-derived xenograft models.

Main Results:

• DNMT3A expression is upregulated in ibrutinib-resistant MCL cells.
• DNMT3A mediates ibrutinib resistance independently of its DNA methylation activity.
• DNMT3A interacts with MEF2B and MYC to induce MYC target genes, promoting OXPHOS.
• Low-dose decitabine treatment inhibits the growth of ibrutinib-resistant MCL cells in vitro and in vivo.

Conclusions:

• DNMT3A plays a critical role in ibrutinib resistance in MCL through metabolic reprogramming.
• Targeting DNMT3A-mediated OXPHOS reprogramming with decitabine is a promising therapeutic strategy for relapsed/refractory MCL.