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

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

PROVIDER: PRJNA554692 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12621925.fastq.gz	Fastqsanger.gz
	SRR12621926.fastq.gz	Fastqsanger.gz
	SRR12621927.fastq.gz	Fastqsanger.gz
	SRR12621928.fastq.gz	Fastqsanger.gz
	SRR9689280.fastq.gz	Fastqsanger.gz

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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:The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anticancer 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 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, which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite the 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 be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a mechanism of evasive resistance in the context of mTOR targeting.

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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

Project description:Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results show that constitutive mTORC1 activation caused by abrogation of TSC2 increases H3K27me3 but not H3K4me3 or H3K9me3, via 4E-BPs-mediated induction of EZH2 protein levels. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects.

2023-11-02 | GSE246887 | GEO

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

2023-11-02 | GSE246886 | GEO

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

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

Project description:MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

Project description:MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [ChIP-Seq]

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MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

Project description:MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors [RNA-Seq]

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mTOR

Project description:mTOR

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Cell cycle plasticity driven by MTOR signaling: integral mechanism for resistance to CDK4/6 inhibition

Project description:Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A to bypass the RB tumor suppressive pathway. This finding and a gene expression profile indicative of a CDK4/6-driven cell cycle suggests that PDAC could be particularly sensitive to CDK4/6 inhibition. Analysis of a panel of patient-derived cell lines and xenografts indicates that many pancreatic cancers have an intrinsic resistance to CDK4/6 inhibition that is not due to known molecular mechanisms. Rather, there is a rapid and potent adaptive response that led to the upregulation of Cyclin D1 and Cyclin E proteins and compromised the suppression of a DNA replication gene expression program. These adaptive responses are dependent on MTOR signaling both in cell and animal studies. Strikingly, combination treatments with MTOR and CDK4/6 inhibitor had potent activity across a large number of patient derived models of PDAC underscoring the potential clinical efficacy.

2019-05-14 | GSE113922 | GEO

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