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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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143363 | GEO | 2020/01/24

REPOSITORIES: GEO

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2019-01-30 | GSE116481 | GEO

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: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

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Project description:The manuscript summarizes clinical and laboratory-based evaluation of 33 AML patients treated with a novel drug combination, venetoclax and azacytidine. Our findings indicate that this regimen is exceptionally promising for the treatment of de novo AML patients. The improvement in outcomes in comparison to conventional therapy is quite remarkable. The manuscript explores the mechanistic basis for the clinical outcomes, testing the hypothesis that venetoclax and azacytidine effectively target leukemia stem cells (LSCs) in vivo. Our findings indicate the regimen is highly active towards the LSC population. Specifically, we describe a mechanism that suppresses the activity of electron transport complex II, resulting in inhibition of oxidative phosphorylation.

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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.

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FOXM1-AKT positive regulation loop provides venetoclax resistance in AML

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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

SUMOylation inhibitor TAK-981 (Subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia

Project description:Acute Myeloid Leukemias (AML) are severe hematomalignancies with dismal prognosis. The post-translational modification SUMOylation plays key roles in leukemogenesis and AML response to therapies. Here, we show that TAK-981 (subasumstat), a first-in-class SUMOylation inhibitor, is endowed with potent anti-leukemic activity in various preclinical models of AML. TAK-981 targets AML cell lines and patient blast cells in vitro and in vivo in xenografted mice with minimal toxicity on normal hematopoietic cells. Moreover, it synergizes with 5-azacitidine (AZA), a DNA-hypomethylating agent now used in combination with the BCL-2 inhibitor venetoclax to treat AML patients unfit for standard chemotherapies. Interestingly, TAK-981+AZA combination shows higher anti-leukemic activity than AZA+venetoclax combination both in vitro and in vivo, at least in the models tested. Mechanistically, TAK-981 potentiates the transcriptional reprogramming induced by AZA, promoting apoptosis, alteration of the cell cycle and differentiation of the leukemic cells. In addition, TAK-981+AZA treatment induces many genes linked to inflammation and immune response pathways. In particular, this leads to the secretion of type I interferon (IFN-I) by AML cells. Finally, TAK-981+AZA induces the expression of Natural Killer (NK)-activating ligands (MICA/B) and adhesion proteins (ICAM-1) at the surface of AML cells. Consistently, TAK-981+AZA-treated AML cells activate NKs and increase their cytotoxic activity. Targeting SUMOylation with TAK-981 may thus be a promising strategy to both sensitize AML cells to AZA and reduce their immune-escape capacities.

2023-08-29 | GSE212330 | GEO

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.

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Hexamethylene Amiloride synergizes with Venetoclax to induce lysosome-dependent cell death in acute myeloid leukemia

Project description:Tumors maintain an alkaline intracellular environment to enable rapid growth. The proton exporter NHE1 participates in maintenance of this pH gradient. However, whether targeting NHE1 could inhibit the growth of tumor cells remains unknown. Here, we report that the NHE1 inhibitor Hexamethylene amiloride (HA) efficiently suppresses the growth of AML cell lines. Moreover, HA combined with venetoclax synergized to efficiently inhibit the growth of AML cells. Interestingly, lysosomes are the main contributors to the synergism of HA and venetoclax in inhibiting AML cells. Most importantly, the combination of HA and venetoclax also had prominent anti-leukemia effects in both xenograft models and bone marrow samples from AML patients. In summary, our results provide evidence that the NHE1 inhibitor HA or its combination with venetoclax efficiently inhibits the growth of AML in vitro and in vivo.

2023-12-31 | GSE247175 | GEO

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