Therapy resistant primitive stem cells in chronic myelogenous leukemia are characterized by low c-Kit expression and altered SCF response
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ABSTRACT:
PROVIDER: PRJNA748415 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15202513.fastq.gz | Fastqsanger.gz | |||
| SRR15202515.fastq.gz | Fastqsanger.gz | |||
| SRR15202517.fastq.gz | Fastqsanger.gz | |||
| SRR15202519.fastq.gz | Fastqsanger.gz | |||
| SRR15202521.fastq.gz | Fastqsanger.gz |
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Project description:Leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) resist elimination with tyrosine kinase inhibitors (TKI) and persist as a source of disease recurrence. LSC populations are heterogeneous, but the most primitive, drug-resistant subsets are not well characterized. Previous studies indicate that variable cell-surface expression of the c-Kit receptor identifies heterogeneous hematopoietic stem cells (HSC) populations. We found that c-Kit expression is reduced on CML LSC compared to normal HSC. Long-term engraftment and leukemia generation capacity was restricted to low c-Kit expressing (c-KitLow) LSC, which showed increased quiescence and inflammatory gene signatures expression. The c-Kit ligand, stem cell factor (SCF), expanded normal HSC but drove maturation of CML LSC. The proportion of c-Kitlow LT-HSC was increased with TKI treatment. Supplementary SCF treatment enhanced elimination of committed but not primitive CML LT-HSC in TKI-treated mice. Low c-Kit expression identifies primitive, treatment-resistant LSC subpopulations with distinct regulatory characteristics, that are critical therapeutic targets.
2022-11-29 | GSE180496 | GEO
Project description:Global phosphoproteomics can reveal signaling cascades in unprecedented detail. The SCF/KIT axis represents a vital hematopoietic receptor tyrosine kinase (RTK) system with gain-of-function mutations prompting the development of mastocytosis and leukemia. Here, we employed a label-free phosphoproteomics profiling strategy to provide the first comprehensive portrayal of SCF-triggered phosphosignaling. Employing untransformed skin-derived mast cells expressing vast amounts of KIT, we uncover around 10,500 class-I-phosphosites following ligand-induced KIT dimerization. Apart from STAT5, the MEK/ERK cascade (including upstream and downstream events) stood out as highly stimulatable by SCF compared to less impacted PI3K/Akt>p38>JNK, a pattern validated by time-resolved immunoblotting. Direct comparison between MEK/ERKÕs and PI3KÕs support of basic programs (anti-apoptosis, cell cycle progression) revealed equipotency with substantial redundancy between the modules. In functional outputs, ERK showed dominance over PI3K regarding cytokine stimulation (TNF-a, IL-8, LIF, OSM) and was the only contributor in the induction of immediate early genes (Fos, JunB, Egr1). Our proteome-wide screen also found Å1,000 phosphosites currently undescribed in databases, pertaining to multiple protein classes. Among candidates, capicua (and components of its network) experienced massive phosphorylation by SCF. Perturbation with capicua by RNA interference unveiled its function as a potent KIT repressor, whose deregulation may contribute to the development of mastocytosis. We demonstrate the utility of an unbiased approach to uncover single protein entities and entire networks activated by RTKs, that can be surveyed experimentally. This rich resource enhances our understanding of RTK-elicited signaling networks and can serve as a benchmark to identify pathological processes, e.g. under circumstances of KIT deregulation.
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Project description:Lung cancer remains the leading cause of cancer-related deaths worldwide. β-arrestin-1 (ARRB1), a scaffolding protein involved in the termination or desensitization of signals arising from activated G-protein-coupled receptors (GPCRs) has been shown to play a role in invasion and proliferation of many cancers, including nicotine-induced proliferation of human non–small cell lung cancers (NSCLCs). In this study, we analyzed nicotine induced and β-arrestin-1 dependent genes from the microarray data. Our analysis show that SCF (Stem cell factor) strongly differentiated smokers from non-smokers implying an important role of this gene in NSCLCs. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene. Here we elucidate the molecular mechanisms by which nicotine as well as EGF induces the expression of SCF in lung adenocarcinoma cell lines A549 and H1650. ChIP assays and transient transfection experiments showed that transcription factor E2F1 can positively regulate SCF expression at the transcriptional level; depletion of E2F1 or β-arrestin-1 prevented the nicotine-mediated induction of SCF. Given that the binding of SCF to c-Kit leads to activation of multiple downstream signaling pathways including Src, PI3K, MEK and EGFR pathways, our data suggest that the SCF plays a central role in lung carcinogenesis, and may be a potential therapeutic target for combating NSCLC. Studies presented here also provide evidence that SCF along with nicotine promotes self-renewal and proliferation of lung cancer stem cells (CSCs). Our findings reveal an important role and prognostic significance of SCF that can serve as a novel prognostic and predictive biomarker for NSCLC.
2013-11-10 | GSE44617 | GEO
Project description:Lung cancer remains the leading cause of cancer-related deaths worldwide. M-NM-2-arrestin-1 (ARRB1), a scaffolding protein involved in the termination or desensitization of signals arising from activated G-protein-coupled receptors (GPCRs) has been shown to play a role in invasion and proliferation of many cancers, including nicotine-induced proliferation of human nonM-bM-^@M-^Ssmall cell lung cancers (NSCLCs). In this study, we analyzed nicotine induced and M-NM-2-arrestin-1 dependent genes from the microarray data. Our analysis show that SCF (Stem cell factor) strongly differentiated smokers from non-smokers implying an important role of this gene in NSCLCs. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene. Here we elucidate the molecular mechanisms by which nicotine as well as EGF induces the expression of SCF in lung adenocarcinoma cell lines A549 and H1650. ChIP assays and transient transfection experiments showed that transcription factor E2F1 can positively regulate SCF expression at the transcriptional level; depletion of E2F1 or M-NM-2-arrestin-1 prevented the nicotine-mediated induction of SCF. Given that the binding of SCF to c-Kit leads to activation of multiple downstream signaling pathways including Src, PI3K, MEK and EGFR pathways, our data suggest that the SCF plays a central role in lung carcinogenesis, and may be a potential therapeutic target for combating NSCLC. Studies presented here also provide evidence that SCF along with nicotine promotes self-renewal and proliferation of lung cancer stem cells (CSCs). Our findings reveal an important role and prognostic significance of SCF that can serve as a novel prognostic and predictive biomarker for NSCLC. Transfection of A549 cell line with control siRNA, Beta arrestin siRNA and then stimulation of nicotine
2013-11-10 | E-GEOD-44617 | biostudies-arrayexpress
Project description:Global phosphoproteomics can reveal signaling cascades in unprecedented detail. The SCF/KIT axis represents a vital hematopoietic receptor tyrosine kinase (RTK) system with gain-of-function mutations prompting the development of mastocytosis and leukemia. Here, we employed a label-free phosphoproteomics profiling strategy to provide the first comprehensive portrayal of SCF-triggered phosphosignaling. Employing untransformed skin-derived mast cells expressing vast amounts of KIT, we uncover around 10,500 class-I-phosphosites following ligand-induced KIT dimerization. Apart from STAT5, the MEK/ERK cascade (including upstream and downstream events) stood out as highly stimulatable by SCF compared to less impacted PI3K/Akt>p38>JNK, a pattern validated by time-resolved immunoblotting. Direct comparison between MEK/ERKÕs and PI3KÕs support of basic programs (anti-apoptosis, cell cycle progression) revealed equipotency with substantial redundancy between the modules. In functional outputs, ERK showed dominance over PI3K regarding cytokine stimulation (TNF-a, IL-8, LIF, OSM) and was the only contributor in the induction of immediate early genes (Fos, JunB, Egr1). Our proteome-wide screen also found Å1,000 phosphosites currently undescribed in databases, pertaining to multiple protein classes. Among candidates, capicua (and components of its network) experienced massive phosphorylation by SCF. Perturbation with capicua by RNA interference unveiled its function as a potent KIT repressor, whose deregulation may contribute to the development of mastocytosis. We demonstrate the utility of an unbiased approach to uncover single protein entities and entire networks activated by RTKs, that can be surveyed experimentally. This rich resource enhances our understanding of RTK-elicited signaling networks and can serve as a benchmark to identify pathological processes, e.g. under circumstances of KIT deregulation.
2022-03-31 | PXD028245 | Pride
Project description:Objective is to identify microRNAs regulated by KIT signaling in mast cells. miRNA profiles of murine bone marrow derived mast cells with and without SCF treatment were compared. In addition, miRNA profiles of the P815 mutant KIT cell line with and without the KIT inhibitor, imatinib, were compared. We identified miRNAs that were differentially regulated by KIT signals.
2011-01-25 | GSE26783 | GEO
Project description:Lung-specific MCEMP1 acts as an adaptor for KIT to promote SCF-mediated mast cell proliferation
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Project description:We analyzed transcriptomic changes in Mcemp1-/- Peritoneal cell-derived mast cells (PCMC) versus Mcemp1 wild-type PCMC cultured with SCF and IL-3 for 9-days.
2023-03-13 | GSE197041 | GEO
Project description:Objective is to identify microRNAs regulated by KIT signaling in mast cells. miRNA profiles of murine bone marrow derived mast cells with and without SCF treatment were compared. In addition, miRNA profiles of the P815 mutant KIT cell line with and without the KIT inhibitor, imatinib, were compared. We identified miRNAs that were differentially regulated by KIT signals. Two systems were used to identify microRNAs regulated by KIT. RNA was collected from primary murine bone marrow derived mast cells (BMMC) treated and not treated with KIT ligand (SCF). In addition, RNA was harvested from the P815 (activating KIT mutation positive) cell line treated and not treated with the KIT inhibitor, imatinib. Samples were harvested after 24 hours of treatment
2011-01-25 | E-GEOD-26783 | biostudies-arrayexpress
Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent CML stem cells persist as a source for recurrence. The effects of TKI treatment on CML stem cell metabolism, and the role of metabolic reprogramming in CML stem cell persistence after TKI treatment are not clear. Here we show that TKI treatment in a CML mouse model leads to acute inhibition of aerobic glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation (OXPHOS) in CML progenitor cells, but that these pathways are restored with continued TKI treatment. Single cell analysis reveals that primitive CML stem cell subpopulations characterized by lower OXPHOS, glycolysis, nucleotide metabolism, and MYC gene signatures are enriched after TKI treatment. TKI treatment initially results in broad inhibition of energy metabolism gene signatures, but continued treatment leads to metabolic reprogramming in persistent stem cells, with enhanced OXPHOS and MYC gene signatures. TKI treatment enhanced HIF-1 activity in quiescent CML stem cells, and addition of a HIF-1 inhibitor significantly depleted CML stem cells in TKI-treated mice. Our results identify mechanisms of metabolic adaptation in CML stem cells following TKI treatment, which can be targeted to deplete persistent quiescent CML stem cells.
2023-08-30 | GSE207346 | GEO