Transcriptomic effects of nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion on human AML cells
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ABSTRACT:
PROVIDER: PRJNA720103 | ENA |
REPOSITORIES: ENA
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Project description:Through integration of whole genome CRISPR screening and pan-cancer genetic dependency mapping, we identified nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) as acute myeloid leukemia (AML) dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, we found that the presence of NAD+ precursors bypassed the dependence of AML on NAMPT, but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. We provide evidence that reduced nuclear NAD+ upon deletion of NMNAT1 activated p53, which is due to attenuated deacetylation by SIRT6/7 in AML cells. Our findings reveal that NAD+ is a critical metabolic foundation for AML, and NMNAT1 is a novel therapeutic target for this disease.
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Project description:Nicotinamide, the amide form of vitamin B3, is essential to maintain the human fetal development. It benefits the ectoderm and endoderm development, but its influence in mesoderm differentiation is elusive. In this study, we reported that nicotinamide regulated the gene expression of cardiovascular system, and it induced functional cardiomyocytes which was independent of canonical WNT signaling. Through a kinase screening, we found that nicotinamide inhibited the activity of P38δ to promote cardiomyocyte differentiation. Furthermore, we compared the gene expression of cardiomyocytes induced by WNT inhibitor IWP-2, nicotinamide or P38 inhibitor SB202190. The results showed that the cardiomyocytes induced by nicotinamide had similar gene expression profile compared with P38 inhibitor, which indicated nicotinamide promoted cardiac differentiation via the inhibition of P38.
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