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Inhibition of pyrimidine biosynthesis targets protein translation in AML

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE181666 | GEO | 2022/04/26

REPOSITORIES: GEO

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Inhibition of pyrimidine biosynthesis targets protein translation in AML.

Project description:The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anti-cancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

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Inhibition of pyrimidine biosynthesis targets protein translation in AML [Targeted_CRISPR_screen]

Project description:Investigating genes that increase or decrease treatment efficacy of AG636 in MLL-AF9; KrasG12D (MN) AML cells.

2022-04-26 | GSE181665 | GEO

Inhibition of pyrimidine biosynthesis targets protein translation in AML [RNA-seq_I1DN]

Project description:Investigation of the transcriptional profile of AML in response to DHODH inhibition by AG636. I1DN model was generated by co-transduction of foetal liver derived HSPCs with constructs encoding IDH1R132H, DNMT3AR882H and NrasG12D. Cells were transplanted into Ptprca recipients. Mice bearing I1DN tumors were treated with AG636 for one day. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated and RNA sequencing performed.

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Inhibition of pyrimidine biosynthesis targets protein translation in AML [RNA-seq_RUNX1]

Project description:Investigation of the transcriptional profile of AML in response to DHODH inhibition by AG636. RUNX1-RUNX1T1 cells were transplanted into Ptprca recipients. Mice bearing tumors were treated with AG636 for one day. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated and RNA sequencing performed.

2022-04-26 | GSE181664 | GEO

Inhibition of pyrimidine biosynthesis targets protein translation in AML [RNA-seq_MN]

Project description:Investigation of the transcriptional profile of MLL-rearranged AML in response to DHODH inhibition by AG636. Chemo-refractory syngeneic murine AML model driven by doxycycline-inducible expression of MLL-AF9 and constitutive expression of oncogenic Nras (MN) was transplanted into Ptprca recipients. Mice bearing MN tumors were treated with doxycycline or AG636 for one or four days. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated and RNA sequencing performed.

2022-04-26 | GSE181661 | GEO

Inhibition of pyrimidine biosynthesis targets protein translation in AML [RNA-seq_MN-2]

Project description:Investigation of the transcriptional profile and compared with the genome accessibility (using ATAC-seq) in MN cells. Mice bearing MN tumors were treated with AG636 for 2 days. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated. RNA sequencing and ATAC-seq were performed.

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Inhibition of pyrimidine biosynthesis targets protein translation in AML [ATAC-seq_MN-2]

Project description:Investigation of the chromatin accessibility in MN cells. Mice bearing MN tumors were treated with AG636 for 2 days. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated. RNA sequencing and ATAC-seq were performed.

2022-04-26 | GSE181660 | GEO

Inhibition of pyrimidine biosynthesis targets protein translation in AML

Project description:Inhibition of pyrimidine biosynthesis targets protein translation in AML

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Inhibition of pyrimidine biosynthesis targets protein translation in acute myeloid leukemia.

Project description:The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

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Inhibition of pyrimidine biosynthesis targets protein translation in AML [Targeted_CRISPR_screen]

Project description:Inhibition of pyrimidine biosynthesis targets protein translation in AML [Targeted_CRISPR_screen]

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