GSE110895 Enhancer remodeling overcomes therapeutic resistance driven by epigenetic evolution in cancer CRISPR screen

Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : OtherOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that therapeutic resistance emerges in the absence of genetic adaptation from leukemia stem cells and whilst the clinical relevance of these findings has been established, what remains unanswered is whether transcriptional programs that confer resistance to therapies are pre-existing or acquired. It is also unclear how stable this adaptive transcriptional response is and whether it can be reversed. Here, we utilize a unique leukaemia model to highlight the key principles of epigenetic resistance. Using single cell RNA-seq with indexed flow sorting, we demonstrate that a form of Lamarckian evolution, namely transcriptional plasticity, drives epigenetic resistance. With a CRISPR-Cas9 screen we identify reciprocal regulators of the enhancer modification H3K4me1/2, LSD1 and MLL4, as important modulators of the resistant cell state. Knockdown or catalytic inhibition of LSD1 causes reversion to a drug sensitive ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Mus musculus Source Type: research

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Abstract Cancer Stem Cells (CSCs) are the subpopulation of cells present in the tumors with capabilities of self-renewal, differentiation, and tumorigenicity when transplanted into an animal host. Therefore, the research work on the CSC has provided a promising approach for the improvement of cancer therapies in the future. The CSCs have a close connection with the cytokines related with the T helper 17 (Th17) cell and other factors present in the tumor microenvironment, and these play a pivotal role in tumor progression and metastasis. The properties of CSCs are well defined in various type of tumor which is main...
Source: Immunology Letters - Category: Allergy & Immunology Authors: Tags: Immunol Lett Source Type: research
Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early ‘90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism and repertoire has followed. These basic notions on NK cells and the...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Miriam M YeungSeries Type : OtherOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that therapeutic resistance emerges in the ab...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously es...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : OtherOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that therapeutic resistance emerges in the absenc...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : OtherOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that therapeutic resistance emerges in the absenc...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously es...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Mus musculus Source Type: research
Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research
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