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FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia

ABSTRACT: FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia

PROVIDER: PRJNA1020175 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26152238_1.fastq.gz	Fastqsanger.gz
	SRR26152238_2.fastq.gz	Fastqsanger.gz
	SRR26152239_1.fastq.gz	Fastqsanger.gz
	SRR26152239_2.fastq.gz	Fastqsanger.gz
	SRR26152240_1.fastq.gz	Fastqsanger.gz

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FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia

Project description:FLT3 is a receptor tyrosine kinase that is frequently mutated in AML. Inhibition of FLT3 induces myeloid differentiation in AML patients. We identified a role of FLT3 inhibition in decreasing EZH2 expression. To assess the impact of this regulation on PRC2 function, we performed H3K27me3 ChIP-Seq in a FLT3 mutated human AML cell line.

2024-01-03 | GSE243857 | GEO

Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

Project description:Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells. It is a target of tyrosine kinase inhibitors (TKIs) used for acute myeloid leukemia treatment. Flt3 and its ligand (Flt3L) are expressed in the heart and cardiac side effects occur under Flt3-targeting TKIs. Whether Flt3/Flt3L also regulate cardiac progenitor cells (CPCs), however, is not known. The cardiac side population (SP) is a pool of heterogenous CPCs that can give rise to all cardiac lineages, hence contributing to cardiovascular homeostasis. Here we show that SP-CPCs produce and are responsive to Flt3L. Compared to wild-type, SP-CPCs from flt3L-/- mice are less abundant, with less contribution of CD45-CD34+ cells, and lower expression of gene sets related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing and compared to wild-type, flt3L-/- Sca1+CD31- SP-CPCs show increased proliferation and less vasculogenic commitment, but differentiation can be induced in the presence of receptor tyrosine kinase-activating growth factors. The observed differences are associated with decreased microvascularisation and global systolic function of flt3L-/- hearts. Thus, Flt3 contributes to a receptor tyrosine kinase signature necessary for the maintenance and functionality of SP-CPCs. These findings have potential implications regarding cardiovascular side effects observed under TKI therapy.

2021-11-30 | GSE168207 | GEO

Glutaminolysis is a metabolic dependency in FLT3 ITD Acute Myeloid Leukemia unmasked by FLT3 Tyrosine Kinase Inhibition

Project description:FLT3ITD are common mutations in Acute Myeloid Leukemia (AML) and carry a particularly bad prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3-mutated AML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3 TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase activating mutations, and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI inhibitors, and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation driven leukemias.

2018-03-07 | GSE105161 | GEO

Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

Project description:Fms-like tyrosine kinase 3 (Flt3) contributes to a receptor tyrosine kinase signature regulating the cardiac side population

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Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

Project description:The type III receptor tyrosine kinase, FLT3 is frequently mutated in acute myeloid leukemia. Phosphorylation of FLT3 on tyrosine residues is a critical event for downstream signaling. Here we studied the role of Y842 residue of FLT3, which is located in the activation loop.

2017-05-02 | E-MTAB-5258 | biostudies-arrayexpress

Gene Expression Profiling of the MLL-AF4 and Flt3 tyrosine kinase domain (TKD) genes in 32Dc cell

Project description:The tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Flt3 gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of MLL leukemia, we investigated synergistic leukemogenesis effects of the two genes in vitro. In a mouse IL3-dependent cell line, 32Dc, the expression of MLL-AF4 and Flt3 TKD was induced using a lentiviral vector. We performed gene expression profiling in the MLL-AF4 and the Flt3 TKD+MLL-AF4 expressing 32Dc cells. The enhancement of Hox genes expression was not identified. However, instead, the expression of S100A6, which was involved in the control of cell proliferation, was synergistically enhanced in the presence of both MLL-AF4 and Flt3 TKD genes. We performed gene expression profiling: 32Dc vs. MLL-AF4 expressing 32Dc, 32Dc vs. Flt3 TKD+MLL-AF4 expressing 32Dc, and MLL-AF4 expressing 32Dc vs. Flt3 TKD+MLL-AF4 expressing 32Dc. A single sample for each expressing cells was analyzed.

2009-03-31 | E-GEOD-14236 | biostudies-arrayexpress

Gene Expression Profiling of the MLL-AF4 and Flt3 tyrosine kinase domain (TKD) genes in 32Dc cell

2009-03-31 | GSE14236 | GEO

Glutaminolysis is a metabolic dependency in FLT3 ITD Acute Myeloid Leukemia unmasked by FLT3 Tyrosine Kinase Inhibition

Project description:Glutaminolysis is a metabolic dependency in FLT3 ITD Acute Myeloid Leukemia unmasked by FLT3 Tyrosine Kinase Inhibition

| PRJNA414977 | ENA

FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.

Project description:Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.

| S-EPMC11141246 | biostudies-literature

Autophagy inhibition impairs leukemia stem cell function in FLT3-ITD AML but has antagonistic interactions with tyrosine kinase inhibition

Project description:The FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML). FLT3 tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy but fail to target leukemia stem cells (LSC) and do not generate sustained responses. Autophagy is an important cellular stress response contributing to hematopoietic stem cells (HSC) maintenance and promoting leukemia development. Here we investigated the role of autophagy in regulating FLT3-ITD AML stem cell function and response to TKI treatment. We show that autophagy inhibition reduced quiescence and depleted repopulating potential of FLT3-ITD AML LSC, associated with mitochondrial accumulation and increased oxidative phosphorylation. However, TKI treatment reduced mitochondrial respiration and unexpectedly antagonized the effects of autophagy inhibition on LSC attrition. We further show that TKI-mediated targeting of AML LSC and committed progenitors was p53-dependent, and that autophagy inhibition enhanced p53 activity and increased TKI-mediated targeting of AML progenitors, but decreased p53 activity in LSC and reduced TKI-mediated LSC inhibition. These results provide new insights into the role of autophagy in differentially regulating AML stem and progenitor cells, reveal unexpected antagonistic effects of combined oncogenic tyrosine kinase inhibition and autophagy inhibition in AML LSC, and suggest an alternative approach to target AML LSC quiescence and regenerative potential.

2022-10-13 | GSE169750 | GEO

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