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Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

ABSTRACT: Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

PROVIDER: PRJNA554691 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9689867.fastq.gz	Fastqsanger.gz
	SRR9689868.fastq.gz	Fastqsanger.gz
	SRR9689869.fastq.gz	Fastqsanger.gz

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Similar Datasets

Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

Project description:mTOR is an important anti-cancer target that integrates diverse signals to control protein synthesis and cell growth. Numerous studies by using mTOR inhibitors and/or gene deletion of mTOR negative regulators have implicated mTOR targeting in suppressing gene expression and cell proliferation. However, we found that gene targeting of mTOR in mouse hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to mTOR loss, mTOR-/- HSCs increase chromatin access and activate global gene expression, in contrast to short-term inhibition by mTOR inhibitors. Such genomic changes are due to a compensatory activation of a MAPK/Mnk/eIF4E signaling pathway that enhances the translation of RNA pol-II and consequent c-myc expression. This adaptive mechanism can also be adopted by leukemia stem cells undergone long-term mTOR inhibitor treatment to confer resistant to mTOR targeting. Our studies provide new insights and a foregone strategy for overcoming drug resistance in mTOR targeted therapy.

2020-12-24 | GSE134317 | GEO

Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anti-cancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR targeted therapies in cancer have seen very limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR-/- HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II (RNAP II), which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can then be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide new insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a novel mechanism of evasive resistance in the context of mTOR targeting.

2020-12-24 | GSE134316 | GEO

Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

| PRJNA554692 | ENA

Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

2021-02-08 | MSV000086816 | MassIVE

Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation

Project description:This SuperSeries is composed of the following subset Series: GSE34537: Mesp1 induces a subset of hematopoietic-associated transcription factors in ES cell-derived Flk1+Tie2+ endothelium GSE34541: Identification of gene targets of Meis2 GSE34543: Identification of gene targets of Meis1 Refer to individual Series

2012-08-02 | E-GEOD-34583 | biostudies-arrayexpress

mTOR

Project description:mTOR

| PRJEB9498 | ENA

Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

Project description:Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GVHD (cGVHD) carrying persistent CD4+ T cell clonal expansion which harbored somatic mTOR, NFKB2, and TLR2 mutations. Functional analysis of the discovered mTOR mutation indicated a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements supported increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggested mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest that somatic mutations may contribute to aberrant T cell proliferations and participate in the persistent immune activation in cGVHD paving the way for novel targeted therapies.

2020-04-12 | E-MTAB-8911 | biostudies-arrayexpress

Effect of a dual specificity PI3K/mTOR inhibitor, NVP-BEZ235, on human ovarian cancer cell lines grown in 3D culture

Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms. Total RNA was isolated 6h and 24h after treatment with 1 M-NM-<M NVP-BEZ235 or DMSO vehicle control from 3D grown structures

2012-03-13 | E-GEOD-28992 | biostudies-arrayexpress

Integrating transcriptome, proteome, and phosphoproteome analysis reveals loss function of IQGAP2 promotes cell proliferation through the mTOR pathway

Project description:Tuberous sclerosis complex (TSC) is a rare genetic disease caused by abnormal of TSC1 or TSC2 gene. Our previous data deduced that IQGAP2 can be one of the genes potentially responsible for non-TSC1 or TSC2 mutation TSC patients. To investigate the pathogenesis of IQGAP2 in TSC, we performed global transcriptome, proteome, and phosphoproteome analyses and found the alter of genes related to mTOR signaling pathway in IQGAP2 knockdown cells. In addition, we found that knockdown of IQGAP2 resulted in increased cell proliferation and enhanced the phosphorylation level of AKT and S6K by functional analysis, meanwhile, the AKT and mTOR inhibitors can partially rescue cell abnormal proliferation by decreasing hyperphosphorylation. Our data revealed a potential connection between mTOR signaling pathway and aberrant cell proliferation in IQGAP2 knockdown cells, and provide a new latent therapeutic strategy for non-TSC1 or TSC2 mutation patients.

2022-09-22 | GSE213715 | GEO

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation and Self-Renewal

Project description:Hematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential is variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings suggest a new molecular basis for HSC control and expansion. Adult mouse bone marrow CD45+EPCR+CD48-CD150+ cells were used in a total of 4 conditions (fresh, 6 hour stimulation with SF+IL-11+UG26 CM, UG26 CM only, SF+IL-11) with 2 technical replicates per condition.

2014-05-01 | E-GEOD-57220 | biostudies-arrayexpress

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