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

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

PROVIDER: PRJNA560975 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10004505_1.fastq.gz	Fastqsanger.gz
	SRR10004505_2.fastq.gz	Fastqsanger.gz
	SRR10004506_1.fastq.gz	Fastqsanger.gz
	SRR10004506_2.fastq.gz	Fastqsanger.gz
	SRR10004507_1.fastq.gz	Fastqsanger.gz

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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

Immune recovery in tumor microenvironment of TP53-mutated AML following venetoclax combination therapy

Project description:The BCL-2 inhibitor venetoclax combined with the hypomethylating agent azacitidine or with low-dose cytarabine significantly improves response rates and overall survival (OS) for newly diagnosed unfit and relapsed / refractory (R/R) acute myeloid leukemia (AML) patients. We retrospectively analyzed our experience with venetoclax combination therapy in 41 unfit AML patients (23 untreated, 18 R/R). Overall response rates were 78.3% for untreated patients and 61.1% for R/R patients. TP53 alterations were observed in 13 patients (31.7%) and were identified as an independent predictor of poor outcome (p=0.0008). We further conducted single-cell RNA sequencing in bone marrow, sampled before and after venetoclax and azacitidine treatment, of three TP53-mutated AML patients who achieved complete remission (CR) or CR with incomplete hematologic recovery. After treatment, numbers of cells expressing anti-apoptotic genes such as BCL2 and MCL1 decreased. CD4 T cells, cytotoxic CD8 T cells, and NK cells significantly increased both in number and in levels of gene expression associated with cytotoxicity post-treatment, confirming immune recovery in the tumor microenvironment. Residual AML cells expressed CD47 and CLEC12A (CLL1). These results indicate that venetoclax combination therapy of AML is promising in real-world clinical practice and suggest a role for ancillary treatment targeting antigens expressed on residual AML cells as a therapeutic strategy in TP53-mutated AML.

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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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Metabolomic and 13C-glucose isotopic profiling data of MOLM14 AML cell line treated with venetoclax, cytarabine or combo and shBCL2.

Project description:We performed quantitative metabolomics and 13C-glucose isotopic profiling experiments on AML MOLM14 cell line following 24h of treatment with venetoclax (50 nM) and aracytine (25 uM) or combination compared to untreated samples. In addition, we also performed quantitative metabolomic experiments on MOLM14 silenced for BCL2 (shRNA).

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Project description:To elucidate the underlying mechanisms of resistance to venetoclax and dexitabine combination therapy, we performed transcriptomic analysis of VEN/DEC pre- and post-treatment samples from AML patients enrolled in the DEC10-VEN clinical trial (NCT03404193). We have reported that AML cells from non-responders show a significant upregulation of the mRNA expression of the fatty acid metabolism activator PPARG (Peroxisome Proliferator-Activated Receptor γ) after VEN/DEC treatment.

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AML patients for in vivo study of venetoclax plus AraC treatment

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Cyclosporine A Enhances the Efficacy of Venetoclax Against FLT3-ITD AML via the PI3K/AKT/mTOR Signaling Pathway

Project description:Acute myeloid leukemia (AML) with the Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for approximately 25-30% of cases and is associated with a poor prognosis, characterized by high relapse rates and significantly reduced overall survival. The use of single-agent venetoclax in FLT3-ITD AML has shown limited efficacy, with drug resistance frequently emerging. In this study, we demonstrate that cyclosporine A (CsA) sensitizes FLT3-ITD AML cells to venetoclax by inhibiting cell proliferation, promoting apoptosis, and disrupting mitochondrial function. Mechanistically, CsA enhances the anti-AML effects of venetoclax by inhibiting NFATC1 through the PI3K/AKT/mTOR signaling pathway. These findings offer promising new therapeutic strategies for managing refractory and relapsed AML, providing a basis for future combination therapies targeting FLT3-ITD mutations.

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GNPS Metabolomic and 13C-glucose isotopic profiling data of MOLM14 AML cell line treated with venetoclax, cytarabine or combo and shBCL2.

2021-07-27 | MSV000087892 | GNPS

Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML

Project description:Acute Myeloid Leukemia (AML) is a blood cancer complicated by acquired drug resistance, disease relapse, and low overall survival rates. Combination therapies using multiple targeted inhibitors can effectively treat AML patients. However, combination treatments are limited by the number of useable targets and our ability to create rational pairings using complimentary molecular mechanisms. Here, we used a human kinase domain-targeted CRISPR screen to identify histone H3 associated protein kinase (HASPIN) as a significant, understudied dependency in AML. HASPIN depletion significantly reduced growth rate, induced a cell cycle arrest, and dysregulated transcription in AML. A proteomics datamining study characterized splicing factors as major HASPIN kinase substrates and highlighted HASPIN’s role as a splicing regulatory kinase. Accordingly, HASPIN depletion strongly dysregulated splicing and inversed aberrant, pro-leukemic splicing programs in AML patients. HASPIN inhibitor CHR-6494 effectively reduced cell viability across AML subtypes while sparing healthy cells. Furthermore, a novel combination therapy consisting of CHR-6494 and BCL-2 inhibitor Venetoclax synergistically reduced AML cell viability and resensitized Venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel, therapeutic target for AML, underscores an underappreciated role in splicing regulation, and proposes a viable combination treatment for clinical use.

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Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax

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