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

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

PROVIDER: PRJNA1187208 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31370600_1.fastq.gz	Fastqsanger.gz
	SRR31370600_2.fastq.gz	Fastqsanger.gz
	SRR31370595_1.fastq.gz	Fastqsanger.gz
	SRR31370595_2.fastq.gz	Fastqsanger.gz
	SRR31370596_1.fastq.gz	Fastqsanger.gz

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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.

2025-06-06 | GSE282105 | GEO

Expression profile of hematopoietic stem and progenitor cell (HSPC) compartment of FLT3-ITD and FLT3-ITD miR-155-/- mice

Project description:The miR-155-dependent differences in gene expression in the HSPC compartment of FLT3-ITD mice is unknown. In this experiment, we performed RNA sequencing on FLT3-ITD and FLT3-ITD miR-155-/- mouse LKS cells.

2017-09-08 | GSE86526 | GEO

CircMYBL2 Regulates FLT3-ITD FLT3AML Translation in AML

Project description:CircMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. We used the ribosome profiling and RNA-seq libraries sequenced with Illumina HiSeq 2500 to identify the mRNA that circMYBL2 targeted. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of PTBP1 to FLT3 mRNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD-positive cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML.

2019-07-09 | GSE133925 | GEO

MS-based phosphoproteomic of cytarabine-treated FLT3-ITD cells

Project description:ITD mutations in the FLT3 gene occur in the 30% of acute myeloid leukemia patients. The integration of ITD in the tyrosine kinase domain (TKD-ITD) of the FLT3 receptor has been shown to confer resistance to standard chemotherapy treatment. We applied state-of-the-art, high-sensitive, mass spectrometry (MS)-based (phospho)proteomics to investigate the molecular mechanisms underlying the sensitivity to cytarabine therapy in FLT3-ITD cells.

2023-07-20 | PXD038638 | Pride

PRMT1-mediated FLT3 arginine methylation promotes FLT3-ITD+ Acute Myeloid Leukemia maintenance

Project description:We want to obtain FLT3-ITD gene signature. To do so, we transduced CB CD34+ cells with mock or FLT3-ITD vectors and performed RNA sequencing (RNA-Seq). Two Groups: Group1: CB CD34+ cells transduced with mock vector; Group2: CB CD34+ cells transduced with FLT3-ITD vector;

2020-04-01 | GSE129754 | GEO

Expression data from KSL and GMP cells of FLT3/ITD and FLT3/ITD-SmoM2 mice

Project description:FLT3/ITD-SmoM2 mice developed rapidly fatal myeloid leukemia compared to FLT3/ITD only mice, suggesting that overactivation of the Hedgehog signaling pathway via SmoM2 can drive myeloid disease progression We used the Affymetrix Mouse 430_2.0 microarray to detail global gene expression responsible for disease progression in sorted bone marrow cells and found that the Hedgehog signaling pathway contributes to disease progression by enhancing FLT3 signaling

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PRMT1-mediated FLT3 arginine methylation is required for maintenance of FLT3-ITD+ Acute Myeloid Leukemia

Project description:The presence of FLT3-ITD mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate FLT3-ITD+ leukemia stem cells (LSCs) which are potential sources of disease relapse, prompting us to ask whether FLT3-ITD protein regulates the AML LSCs survival through a kinase-independent mechanism. Here, we show that expression of PRMT1, the primary type I arginine methyltransferase, significantly increases in LSC-enriched CD34+CD38- populations relative to normal counterparts. Genetic PRMT1 depletion blocked AML CD34+ cell survival, and had more potent effects in AML cells from patients harboring FLT3-ITD. Our genome wide analysis of gene expression and PRMT1 conditional KO mouse study confirmed that PRMT1 preferentially cooperates with FLT3-ITD contributing to AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginines 972/973, and PRMT1 promoted leukemia cell growth in a FLT3 methylation-dependent manner. Moreover, effects of FLT3-ITD methylation in AML cells were in part due to crosstalk with FLT3-ITD phosphorylation at tyrosine 969 (Y969). Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following TKI (AC220) treatment, indicating that methylation occurs independently of kinase activity. Finally, in both patient-derived xenograft (PDX) and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes LSC activity and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to selectively target FLT3-ITD+ LSCs.

2021-11-10 | GSE122435 | GEO

Enhancer chromatin marks in Dnmt3aKO/FLT3-ITD lymphoid leukemia

Project description:We mapped H3K4me1 and H3K27ac chromatin marks in Dnmt3aKO/FLT3-ITD and FLT3-ITD lymphoid leukemias

2016-05-19 | GSE80723 | GEO

identifying mRNA expression regulated by FLT3/ITD and Cxcl12

Project description:mRNA expression regulated by FLT3/ITD and Cxcl12 were compared in the Ba/F3 cells expressing wild type FLT3 or FLT3/ITD and incubated with or without Cxcl12.

2021-06-09 | GSE176401 | GEO

RNA sequencing of MV4;11 cells harbouring FLT3-ITD mutations

Project description:The purpose of the experiment is to investigate whether more co-mutations exists in MV4;11 cells harboring FLT3-ITD/D835 than cells with FLT3-ITD only.

2023-05-27 | GSE151249 | GEO

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