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Comparative RNA sequencing identifies superior cytocidal mechanisms of imatinib over rapamycin in UMB1949 renal angiomyolipoma cells

ABSTRACT: We report results of RNA sequencing analysis of serum starved UMB1949 renal angiomyolipoma (AML) cells comparatively treated for 24hrs at 37C and 5% CO2 with rapamycin (0.05uM and 1uM) and tyrosine kinase inhibitor (TKI) imatinib (1uM and 10uM). Experiments were done in triplicates per drug concentration. This study was performed to investigate the biological mechanisms underlying superior cytocidal capabilities of the TKI over FDA-approved rapamycin by inhibiting receptor tyrosine kinases on mesenchymal tumorigenic cells in Tuberous Sclerosis and Lymphangioleiomyomatosis (LAM) diseases. Total RNA isolates (RIN>8.0) were sequenced on an illumina Novaseq6000 platform at 100 base pairs to a depth of 30 milllion single end reads. Real-Time Analysis was used for base callling converted to fastq format with bcl2fastq2. Pseudoalignment of RNA-seq reads to a kallisto index was created from human reference genome NCBI/GRCh38.p13. Reads were also mapped to this reference genome using STAR (2.5.2b) and featureCounts (v1.5.0-p3) for results comparison. Differential expression was resolved using Sleuth and DESeq2 in R and signaling pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Results reveal differential inactivation of the GPVI pathway and key cell survival and viability genes only in renal AML cells treated with imatinib conentrations.We further determined that this TKI differentially induced ER calcium efflux that disrupted mitochondrial permeability leading to increased cytosolic cytochrome C, caspase 3 activation and apoptosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193402 | GEO | 2022/01/15

REPOSITORIES: GEO

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Comparative RNA sequencing identifies superior cytocidal mechanisms of imatinib over rapamycin in Pulmonary Lymphangioleiomyomatosis (LAM) Tumor Cells

Project description:We report results of RNA sequencing analysis of serum starved pulmonary LAM tumor cells comparatively treated for 24hrs at 37C and 5% CO2 with rapamycin (0.05uM and 1uM) and tyrosine kinase inhibitor (TKI) imatinib (1uM, 5uM, and 10uM). Experiments were done in duplicates per drug concentration. This study was performed to investigate the biological mechanisms underlying superior cytocidal capabilities of the TKI over FDA-approved rapamycin by inhibiting receptor tyrosine kinases on mesenchymal tumorigenic cells in Tuberous Sclerosis and Lymphangioleiomyomatosis (LAM) diseases. Total RNA isolates (RIN>8.0) were sequenced on an illumina Novaseq6000 platform at 100 base pairs to a depth of 20 milllion paired end reads. Real-Time Analysis was used for base callling converted to fastq format with bcl2fastq2. Pseudoalignment of RNA-seq reads to a kallisto index was created from human reference genome NCBI/GRCh38.p13. Differential expression was resolved using Sleuth in R and signaling pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Results reveal differential inactivation of the Cell Cycle: G2/M DNA Damage Checkpoint Regulation SIgnaling Pathway only in pulmonary LAM tumor cells treated with 10uM imatinib concentration.We further determined that increasing imatinib conentrations from 1uM to 10uM induced endoplasmic reticulum inositol triphosphate receptor (IP3R) subtype switching from type I to type III typically associated with differential ER calcium efflux and apoptosis.

2022-01-15 | GSE193398 | GEO

Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI. Three Ph+ ALL cell lines (BV-173, SUP-B15 and TOM-1) were treated in the presence or absence of 10 μM STI571 (Imatinib) or in the presence of both 10 μM STI571 and 20 μM RI-BPI for 24 hours.

2011-03-01 | E-GEOD-24381 | biostudies-arrayexpress

Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia

2011-03-01 | GSE24381 | GEO

The effect of PPARG inhibition on human angiomyolipoma cells

Project description:Angiomyolipoma (AML), the most common benign renal tumor, can result in severe morbidity from hemorrhage and renal failure. While mTORC1 activation is involved in its growth, mTORC1 inhibitors fail to eradicate AML, highlighting the need for new therapies. Moreover, the identity of the AML cell of origin is obscure. AML research, however, is hampered by the lack of in-vivo models. Here, we establish a human AML-xenograft (Xn) model in mice, recapitulating AML at the histological and molecular levels. Microarray analysis demonstrated tumor growth in-vivo to involve robust PPARG-pathway activation. Similarly, immunostaining revealed strong PPARG expression in human AML specimens. Accordingly, we demonstrate that while PPARG agonism accelerates AML growth, PPARG antagonism is inhibitory, strongly suppressing AML proliferation and tumor-initiating capacity, via an anti-TGFb mechanism. Finally, we show striking similarity between AML cell lines and multipotent mesenchymal stromal cells (MSCs) in terms of antigen and gene expression and differentiation potential. Altogether, we establishment the first in-vivo human AML model, provide evidence that AML may originate in a PPARG-activated renal MSC lineage that is skewed towards adipocytes and smooth muscle and away from osteoblasts, and uncover PPARG as a regulator of AML growth, which could serve as an attractive therapeutic target.

2017-02-04 | GSE94461 | GEO

Global gene expression changes during human Angiomyolipoma xenograft propagation

2017-02-28 | GSE94114 | GEO

Whole-genome gene expression comparison of the chronic myeloid leukemia cell line K562 and its tyrosine kinase inhibitor resistant subclone K562-IR.

Project description:The aim of the analysis is to study the relationship between tyrosine kinase inhibitor (TKI) resistance mechanism and phenotypic plasticity in the TKI-resistant and parental chronic myeloid leukemia K562 cell lines, in the presence and absence of imatinib. Results provide insight into the molecular mechanisms underlying the acquisition of cancer cell plasticity.

2020-04-14 | GSE120932 | GEO

Chronic myeloid leukaemia stem cells present an aberrant gene expression signature that is not affected by tyrosine kinase inhibitors

Project description:Tyrosine kinase inhibitors (TKI) revolutionised the treatment of CML at the beginning of the century. However, TKI do not eliminate the leukaemia stem cells, which can reinitiate the disease upon treatment withdrawal. Thus, finding new therapeutic targets in CML stem cells is key to find a curative treatment. Using microarray datasets, we defined a list of 227 genes which were differentially expressed in CML stem cells compared to healthy controls but were not affected by TKI. Two of them, CD33 and PPIF, are targeted by gemtuzumab-ozogamicin and cyclosporin A, respectively. We treated CML and control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI independent gene expression signature. Cyclosporine A in combination with imatinib reduced the number of CML CFC compared with non-CML controls, but at concentrations not achievable in the clinical practice. Gemtuzumab-ozogamicin showed a EC50 of 146ng/mL, well below the plasma peak concentration of 630ng/mL observed in AML patients and below the EC50 of 3247ng/mL observed in non-CML cells. Interestingly, gemtuzumab-ozogamicin seems to promote cell cycle progression in CML CD34+ cells and we found it to activate the RUNX1 pathway in a RNAseq experiment. This suggests that targeting the tyrosine kinase inhibitor independent gene expression signature in CML stem cells could be exploited for the development of new therapies in CML.

2022-11-14 | GSE198576 | GEO

Recruitment of BCL6 to target genes in Philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we used genome tiling arrays to identify BCL6 target genes with specific recruitment of BCL6. Three Ph+ ALL cell lines (BV-173, NALM-1 and TOM-1) in duplicate were either treated with 10µM STI571 (Imatinib) for 24 hours or cultured in absence of STI571.

2011-02-15 | E-GEOD-24404 | biostudies-arrayexpress

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

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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