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AML patients for in vivo study of venetoclax plus AraC treatment

ABSTRACT: AML patients for in vivo study of venetoclax plus AraC treatment

PROVIDER: PRJNA760235 | ENA |

REPOSITORIES: ENA

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AML patients for in vivo study of venetoclax plus AraC treatment

Project description:Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a “MitoScore” signature that identifies high mitochondrial oxidative phosphorylation (OxPHOS) in vivo and in AML patients. Primary AML cells with cytarabine (AraC) resistance and high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) plus AraC (but not to VEN plus azacytidine, AZA). Single-cell transcriptomics of VEN+AraC-residual cell populations revealed adaptive resistance associated with changes in OxPHOS, electron transport chain complex (ETC) and the TP53 pathway.

2021-11-12 | GSE183329 | GEO

In vivo study of venetoclax plus AraC treatment

Project description:3 different MOLM14 cell line xenografts (CLDXs) on NSG mice, treated with venetoclax plus AraC.

2021-11-12 | GSE181792 | GEO

In vivo study of venetoclax plus AraC treatment

Project description:In vivo study of venetoclax plus AraC treatment

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Single-Cell RNA-Seq Datasets of residual AML cells purifed from Patient Derived Xenograft bone marrow treated or not with venetoclax plus cytarabine [Patient TUH69]

Project description:The goal of this study is to compare single cell transcriptome of in vivo AML cells profiling before treatment and after venetoclax and cytarabine in single agent or after the duplet. This study uncovered transcriptionally different cell subpopulations that specifically emerge in VEN+AraC residual disease.

2021-06-26 | GSE178911 | GEO

Single-Cell RNA-Seq Datasets of residual AML cells purifed from Patient Derived Xenograft bone marrow treated or not with venetoclax plus cytarabine [Patient TUH07]

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CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) of paired diagnosis and relapse specimens from acute myeloid leukemia (AML) patients treated with venetoclax plus azacitidine

Project description:To understand relapse mechanisms related to AML patients treated with venetoclax plus azacitidine therapy, we performed CITE-seq on paired diagnosis and relapse specimens from an AML patient treated with the therapy.

2020-01-24 | GSE143363 | GEO

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

2019-05-03 | GSE125403 | GEO

Effect of venetoclax, tedizolid, and combination treatment on gene expression in a venetoclax-resistant AML cell line

Project description:The goal of this study was to profile the changes in gene expression in an AML cell line with acquired resistance to venetoclax in response to treatment with venetoclax, tedizolid, or combination of the 2 drugs.

2019-08-20 | GSE136032 | GEO

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax

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Gene expression of AML patient samples

Project description:It has been hypothesized that chemotherapy resistant human acute myeloid leukemia (AML) cells are enriched in an immature phenotype, cellular quiescence and leukemic initiating cells (LICs). However, these hypotheses have never been validated completely in vivo. We have developed a physiologically relevant chemotherapeutic approach with cytosine arabinoside AraC using patient-derived xenograft (PDX) models. AraC-treated AML cells are not consistently enriched for either immature cells or quiescent cells. AraC treatment does not enrich for LICs as measured by limiting dilution in secondary transplantations. Rather chemotherapy resistant cells in vivo have high levels of reactive oxygen species (ROS) and a gene signature consistent with oxidative phosphorylation (OXPHOS). Treatment of human HIGH OXPHOS but not LOW OXPHOS AML cell lines showed chemotherapy resistance in vivo, showing that essential mitochondrial functions make significant contributions to AraC resistance in AML. Accordingly, targeting mitochondrial OXPHOS metabolism through the inhibition of mitochondrial protein synthesis, the electron transfer chain or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and strongly enhanced anti-leukemic effects of AraC in AML cells. These results demonstrate that chemotherapy resistance in AML is not necessarily associated with stemness but is highly dependent on a distinct oxidative metabolism, and that the HIGH OXPHOS gene signature is a robust hallmark of the AraC response in PDX and a promising therapeutic avenue to treat AML residual disease.

2017-06-25 | GSE97393 | GEO

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