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Genomewide Screen Reveals Potential Synergistic Partners for FLT3 Mutant Myeloid Leukemia

ABSTRACT: Genomewide Screen Reveals Potential Synergistic Partners for FLT3 Mutant Myeloid Leukemia

PROVIDER: PRJNA600003 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10852434.fastq.gz	Fastqsanger.gz
	SRR10852435.fastq.gz	Fastqsanger.gz
	SRR10852436.fastq.gz	Fastqsanger.gz
	SRR10852437.fastq.gz	Fastqsanger.gz
	SRR10852438.fastq.gz	Fastqsanger.gz

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Genomewide Screen Reveals Potential Synergistic Partners for FLT3 Mutant Myeloid Leukemia

Project description:CRISPR knockout screening on MOLM-13 cells with midostaurin or gilteritinib

2020-01-09 | GSE143314 | GEO

Combinatorial inhibition of Notch and FLT3 exerts synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Project description:we observed synergistic cytotoxic effects, preferentially reducing cell proliferation and inducing apoptosis in FLT3/ITD+ AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in a FLT3/ITD+ patient derived xenograft (PDX) AML model. Mechanistically, decreased expression of CXCR3 that lead to down-regulated ERK signaling was partially responsible for the observed synergy. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD+ AML.

2019-02-23 | GSE126933 | GEO

Synergistic Targeting of FLT3 Mutations in AML via Combined Menin-MLL and FLT3 Inhibition

Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

2020-07-01 | GSE144759 | GEO

Genomewide T. brucei RNAi screen using proteasome inhibitor

Project description:Genomewide T. brucei RNAi screen using proteasome inhibitor

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Synergistic Targeting of FLT3 Mutations in AML via Combined Menin-MLL and FLT3 Inhibition

Project description:Synergistic Targeting of FLT3 Mutations in AML via Combined Menin-MLL and FLT3 Inhibition

| PRJNA604804 | ENA

Combinatorial inhibition of Notch and FLT3 exerts synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Project description:Combinatorial inhibition of Notch and FLT3 exerts synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

| PRJNA523802 | ENA

Genome-wide CRISPR-Cas9 screen identifies protein-coding genes and microRNAs important in FLT3-ITD+ AML (MV4-11) cellular growth

Project description:The functional relevance of many microRNAs in the context of tumor biology remains unclear. Using CRISPR-Cas9 technology, we performed a global loss-of-function screen to test the impact of individual microRNAs on the growth of FLT3-ITD positive leukemia cells. This approach identified both evolutionarily conserved and non-conserved human microRNAs that function to suppress or promote tumor cell growth, revealing that microRNAs are extensively integrated into the molecular networks that control tumor cell physiology. Our study describes a powerful genetic approach by which the function of individual microRNAs can be assessed on a global level, and its use will rapidly advance our understanding of how microRNAs contribute to human disease. Loss-of-function CRISPR-Cas9 screen identifies genes whose loss leads to increased or decreased FLT3-ITD+ cell growth over 23 day time-course

2016-07-01 | E-GEOD-71539 | biostudies-arrayexpress

In-Depth Proteomics Reveals Selective EV Protein Sorting and Pathway Perturbation in AML upon Synergistic FLT3 and Hedgehog Pathway Inhibition

Project description:Acute myeloid leukemia (AML) is an aggressive cancer mainly affecting bone marrow and blood with a high relapse incidence and mortality rate. Approximately one third of AML patients carry an fms-like tyrosine kinase 3 (FLT3) mutation, which is often associated with GLI expression and Hedgehog signaling, leading to tumor proliferation. AML cells shape their microenvironment into a leukemia-permissive space by releasing extracellular vesicles (EVs). EVs can transfer chemoresistance and thereby play an important role in refractory and relapsing diseases. Here, we discovered a synergistic effect of a combined treatment with the FLT3 inhibitor Crenolanib and the Hedgehog pathway inhibitor HPI-1 in the AML cell lines MOLM-14 and MV4-11. In-depth comparative proteomics revealed alterations in the cellular and the EV proteome upon single or combined inhibition of FLT3 and GLI, highlighting affected pathways. By comparing the cellular and EV proteomes, we report that transport of ribosomal proteins such as RPS26 and RPL27A and ErbB pathway members such as GAB1, GRB2 and SHC1 to EVs is selectively avoided upon treatment with Crenolanib. Ribosomal and ErbB signaling pathway proteins may play an important role in microenvironmental modulation by EVs, and Crenolanib treatment potentially acts by interfering with leukemia niche formation.

2025-09-29 | PXD061404 | Pride

A genome-wide CRISPR screen identifies genes critical for resistance to FLT3 inhibitor AC220

Project description:To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR pooled library to screen new genes whose loss of function confers resistance to AC220. In our screen, we identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated that re-activation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to the FLT3 inhibitor. We also confirmed our findings in primary AML patient samples. We demonstrated that the expression level of SPRY3 and GSK3A is dramatically reduced in AC220 resistant AML samples and SPRY3 deleted primary AML cells are resistant to AC220. Intriguingly, we found that expression of SPRY3 is greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function confers resistance to a selective FLT3 inhibitor and revealed the underlying mechanism, thereby providing new insight into signaling pathways that contribute to the acquired resistance in AML.

2017-05-06 | GSE98612 | GEO

Epigenetic regulation of FLT3 by ZNF384-fusion protein

Project description:Profiling global gene expression in large ALL cohorts, we identified unique over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discovered an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There was also a striking global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells.

2022-08-11 | GSE197890 | GEO

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