Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Abstract

Control of cellular identity involves coordination of developmental programs with environmental factors such as nutrient availability, suggesting that modulating aspects of metabolism could enable therapeutically relevant changes in cell fate. We show that nucleotide depletion facilitates gene expression changes towards a new cell fate by perturbing DNA replication in models of acute myeloid leukemia, a cancer characterized by a differentiation blockade. This transition starts in S phase and is independent of replication stress signaling and DNA damage signaling pathways. Moreover, it occurs despite sustained oncogene-driven expression of the progenitor program and is accompanied by limited changes in chromatin accessibility. Altering lineage-determining transcription factor expression redirects cell fate progression towards an alternate fate upon replication stress, suggesting that perturbing DNA replication allows cells to mobilize primed maturation programs. Our work, along with other findings in diverse systems, suggests a conserved mechanism by which metabolic changes can orchestrate cell fate transitions.

Mitochondrial folate metabolism inhibition drives differentiation through mTORC1 mediated purine sensing

“…These data suggest that impairment of pyrimidine biosynthesis induces differentiation through a separate mechanism, independently of mTORC1 signalling. Indeed, in agreement with our data, it has been recently suggested that pyrimidine depletion alters cell fate of AML cells through DNA replication stress 49…”

“…These data suggest that impairment of pyrimidine biosynthesis induces differentiation through a separate mechanism, independently of mTORC1 signalling. Indeed, in agreement with our data, it has been recently suggested that pyrimidine depletion alters cell fate of AML cells through DNA replication stress 49 In terms of clinical relevance, we found that folate metabolism inhibition synergises with TKI treatment to target therapy insensitive LSCs. Resistance of LSCs to standard therapy has been associated with their undifferentiated and quiescent state 50,51 .…”

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

“…3c, d). Therefore, although pyrimidine synthesis inhibition can be associated with myeloid leukemia differentiation 18 , it is not likely to be the metabolic driver of the erythroid differentiation we observe here.…”

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis

“…S4, C and D). Therefore, although pyrimidine synthesis inhibition can be associated with myeloid leukemia differentiation ( 28 ), it is not likely to be the metabolic driver of the erythroid differentiation we observe here. In addition, the ratio of glutathione/oxidized glutathione does not change significantly, and the reduced form of nicotinamide adenine dinucleotide phosphate (NADP + ) (NADPH)/NADP and reduced form of nicotinamide adenine dinucleotide (oxidized form) (NAD + ) (NADH)/NAD ratios are significantly higher in K562 after 8 days in 100 nM FA.…”