Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [RNAseq_AG120_AZA_treatment]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA832585 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18936401.fastq.gz | Fastqsanger.gz | |||
| SRR18936402.fastq.gz | Fastqsanger.gz | |||
| SRR18936403.fastq.gz | Fastqsanger.gz | |||
| SRR18936404.fastq.gz | Fastqsanger.gz | |||
| SRR18936405.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201661 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201663 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201662 | GEO
Project description:Acute myeloid leukemia (AML) tumors are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 or -2 that result in over-production of the onco-metabolite D-2-hydroxyglutarate (2-HG). Small molecule inhibitors that block 2-HG synthesis can induce complete morphological remission even in heavily pre-treated AML patients. However, almost all patients eventually relapse with analysis of clinical samples suggesting that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 (Ivosidenib) at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that inhibition of mutant IDH1 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although single agent AG-120 treatment was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells (LSCs) and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to the cytosine analogue hypomethylating agent azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non-genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.
2022-08-17 | GSE201664 | GEO
Project description:Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells
| PRJNA832580 | ENA
Project description:Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [RNAseq_AG120_treatment]
| PRJNA832588 | ENA
Project description:Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [RRBS]
| PRJNA832586 | ENA
Project description:Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [scRNA-seq]
| PRJNA832587 | ENA
Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism for the induction of granulocytic differentiation and cell death following inhibition of IDH1 mutant protein in primary AML cells, we performed gene expression microarrays following treatment with either GSK321 IDH1 inhibitor or Controls (DMSO or GSK990 inactive inhibitor). Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO. Followed by microarray analysis after RNA extraction.
2015-09-21 | E-GEOD-72152 | biostudies-arrayexpress
Project description:Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in AML patients’ cells. Our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia. To obtain insight into the molecular mechanism of the novel IDH1 mutant allosteric inhibitor, primary AML cells were treated with either GSK321 IDH1 active inhibitor or Controls (DMSO or GSK990 inactive inhibitor) followed by DNA extraction for ERRBS analysis. Primary IDH1 mutant acute myeloid leukemia (AML) mononuclear (MNC) cells were treated in suspension cultures in differentiating media for 6 days with 3 microM GSK990 or GSK321 and an equal volume of DMSO, Followed ERRBS analysis after DNA extraction.
2015-09-21 | E-GEOD-72247 | biostudies-arrayexpress