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that restored both UTP and CTP pools, prevented induction of terminal differentiation by the DHODH inhibitor leflunomide, while neither deoxycytidine nor deoxythymi- dine could do this.7 CTP is the ribonucleotide present at lim- iting concentrations in our cells, having concentrations ~3- fold lower than those of UTP or guanosine triphosphate (GTP), and ~30-fold lower than the concentration of adeno- sine triphosphate (ATP).8 CTP is also the ribonucleotide most upregulated in cancer versus normal cells, mediated at least in part by upregulation of CTPS2.8,9
It is of course no surprise that basic building blocks such as CTP are essential for cell proliferation, including malig-
nant proliferation. But how is CTP linked to lineage pro- gression? Several mitochondrial products serve as cofactors for key epigenetic enzymes that remodel lineage-differenti- ation genes for activation or repression (Figure 1B).10 Alpha- ketoglutarate (AKG) is an essential cofactor for dioxygenas- es including TET DNA methylcytosine dioxygenases, and Jumonji domain-containing histone demethylases (KDM), which are components of multiprotein complexes (coacti- vators) that remodel chromatin to activate terminal differ- entiation genes. Acetyl-CoA is a cofactor for histone lysine acetyltransferases (HAT), which are also coactivator com- ponents. Flavin adenine dinucleotide (FAD) is a cofactor for
AB
Figure 1. The dihydroorotate dehydrogenase inhibitor ASLAN003 recapitulates in acute myeloid leukemia cells the coordinated up- and down-regulation of thou- sands of genes that occurs with normal terminal granulocyte or monocyte differentiation. (A) The 1,000 genes most significantly up- or down-regulated upon addi- tion of ASLAN003 to KG1 or MOLM14 acute myeloid leukemia (AML) cells were examined for their expression pattern in normal hematopoietic stem cells (HSC), multi- potent progenitors (MPP), common myeloid progenitors (CMP), granulocyte-monocyte progenitors (GMP), granulocytes (gran) and monocytes (mono) (data from BloodPool15), and found to be genes normally up- or down-regulated with terminal granulocyte or monocyte differentiation. Experimental details of ASLAN003 treat- ment are described by Zhou et al.,1 gene expression by RNA-sequencing Geo Database GSE128950. (B) Proliferation and lineage differentiation are coupled through mitochondrial metabolism. AKG: alpha-ketoglutarate; Ac-CoA: acetyl-CoA; FAD: flavin adenine dinucleotide; NAD+: nicotinamide adenine dinucleotide; CTP: cytidine triphosphate. The putative epigenetic protein in eukaryotic cells for which CTP is a cofactor is unknown. (C) The dihydroorotate dehydrogenase (DHODH) inhibitor ASLAN003 acutely reconfigures pyrimidine metabolism in KG1 and MOLM14 AML cells (data from GSE1289501). Analysis using Broad Institute Morpheus software, P-value Marker Selection, 100 permutations.
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haematologica | 2020; 105(9)