NAM-NAD+-ADO metabolic reprogramming is a key factor for DNMT3A mutation to promote leukemia development through regulating cell cycle and immune microenvironment

Abstract

DNMT3A-R882H mutation is a frequent epigenetic mutation in acute myeloid leukemia (AML)-M4 and M5, participating in the regulation of cell growth and differentiation by blocking the binding of transcription factor complexes to DNA. However, effective approaches that directly target this inactivating mutation for therapy remain lacking. For the first time, we show that the DNMT3A-R882H mutation can switch leukemia cells to undergo nicotinamide (NAM) and nicotinamide adenine dinucleotide (NAD+) metabolism and influence the formation of cyclin-CDK complexes by affecting the deacetylation function of SIRT6. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) can reduce the NAD + required for SIRT6 function, degrade CDKN1A/CDKN1B, and effectively induce cell cycle arrest and apoptosis. The NAMPT inhibitor FK866 can optimize the immune-infiltrating microenvironment by reducing the production of the downstream metabolite adenosine (ADO). Animal experiments have shown that NAMPT inhibition or knockdown can significantly inhibit tumor cell growth, reduce spleen infiltration of tumor cells, and prolong mouse lifespan. Our findings provide a potential direction for a targeted therapy at the metabolic level in AML with DNMT3A mutations.