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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE181665 | GEO | 2022/04/26

REPOSITORIES: GEO

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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 [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 [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.

2022-04-26 | GSE181662 | GEO

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_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.

2022-04-26 | GSE181663 | GEO

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.

| S-SCDT-EMM-2021-15203 | biostudies-other

Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9

Project description:To explore oncogene addiction programs in a genetically defined leukemia context we developed an AML mouse model driven by a conditional MLL-AF9 allele together with oncogenic Ras, which enabled us to examine the consequences of MLL-AF9 inhibition in established disease. In order to produce a tightly regulated system that was easy to monitor, we constructed two retroviral vectors containing dsRed-linked MLL-AF9 under control of a tetracycline response element promoter, and KrasG12D or NrasG12D linked to the “Tet-off” tet-transactivator, which activates TRE expression in a doxycycline repressible manner. Leukemias were generated by retroviral cotransduction of both vectors into hematopoietic stem and progenitor cells, which were transplanted into syngeneic mice. Cells harboring both constructs induced aggressive myelomonocytic leukemia. Five independent primary leukemia cell lines were established from bone marrow of terminal mice. Treatment of these lines with doxycycline rapidly turned off MLL-AF9 expression, and induced terminal myeloid differentiation and complete disease remission in vivo. To identify molecular mechanisms underlying addiction to MLL-AF9, we analyzed global gene expression changes following doxycycline-induced suppression of MLL-AF9. Independent primary acute myeloid leukemia lines induced by cotransduction of Tet-off MLL-AF9 together with either KrasG12D or NrasG12D were grown in culture and treated with doxycycline for 6 days to inactivate MLL-AF9 expression. In addition, primary acute myeloid leukemia lines with constitutive MLL-AF9 and KrasG12D were included to control for the effects of doxycycline. Untreated and treated cells were harvested for RNA extraction and hybridization to Affymetrix arrays.

2011-08-04 | E-GEOD-30746 | biostudies-arrayexpress

Inhibition of pyrimidine biosynthesis targets protein translation in AML

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-04-26 | GSE181666 | GEO

POLR2M-mediated paused transcription silences tumor suppressor MIR139 in MLL-AF9 AML

Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.

2021-11-11 | PXD022488 | Pride

AML mouse models

Project description:This SuperSeries is composed of the following subset Series: GSE30745: Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb GSE30746: Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9 Refer to individual Series

2011-08-04 | E-GEOD-30747 | biostudies-arrayexpress

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