Similar Datasets
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 | 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 | 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 [RNAseq_AG120_AZA_treatment]
| PRJNA832585 | ENA
Project description:Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.
| S-EPMC8063727 | biostudies-literature
Project description:Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells [scRNA-seq]
| PRJNA832587 | ENA