Molecular targeting of inosine-5’-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway

Ichii, Michiko; Oritani, Kenji; Murase, Masao; Komatsu, Kensuke; Yamazaki, Mao; Kyoden, Rie; Kito, Nobuko; Nozaki, Yusuke; Saito, Motoki; Iwamura, Hajime; Kanakura, Yuzuru

doi:10.1080/10428194.2017.1339878

Cited by 5 publications

(2 citation statements)

References 32 publications

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“…Previous studies in erythroleukemia have shown that both purine supplementation (29,30) and inhibition of purine synthesis (31,32) can induce erythroid differentiation. Therefore, the early inhibition of purine synthesis led us to hypothesize that perturbation of this pathway drives a stress response that results in erythroid cell differentiation.…”

Section: Purine Biosynthesis Inhibition Is An Early Event Following F...mentioning

confidence: 99%

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

Maynard,

Pohl,

Mueller

et al. 2024

Sci. Adv.

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Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5′-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5′-monophosphate–activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation–induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency–induced anemia.

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Section: Purine Biosynthesis Inhibition Is An Early Event Following F...mentioning

confidence: 99%

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

Maynard,

Pohl,

Mueller

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

show abstract

“…Previous studies in erythroleukemia have shown that both purine supplementation 19,20 and inhibition of purine synthesis 21,22 can induce erythroid differentiation. Therefore, the early inhibition of purine synthesis led us to hypothesize that perturbation of this pathway drives a stress response that results in erythroid cell differentiation.…”

Section: Purine Biosynthesis Inhibition Is An Early Event Following F...mentioning

confidence: 99%

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

Maynard

Pohl

Petrova

et al. 2022

Preprint

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All dividing cells require the essential vitamin folate. Hematopoietic cells harbor a unique sensitivity to folate deprivation, as implied by the development of folate-deficient anemia and the utility of anti-folate chemotherapy in blood cancer. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines, as well as primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis that is followed by enhanced heme metabolism, hemoglobin synthesis and erythroid differentiation. This finding is phenocopied by inhibition of folate metabolism using SHIN1, an inhibitor of the folate enzymes SHMT1/2. The metabolically-driven differentiation is rescued by supplementation of purine precursors, yet occurs independent of nucleotide sensing through mTORC1 and AMPK. Our work profiles the metabolic response to folate depletion in erythroid cells and suggest that premature differentiation of folate-deprived erythroid progenitor cells is a mechanistic etiology to folate-deficiency induced anemia.

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FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in hematological malignant cells

et al. 2019

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Molecular targeting of inosine-5’-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway

Cited by 5 publications

References 32 publications

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

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

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

FF-10501 induces caspase-8-mediated apoptotic and endoplasmic reticulum stress-mediated necrotic cell death in hematological malignant cells

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