GSE122843 Enhancer remodeling overcomes therapeutic resistance driven by epigenetic evolution in cancer single cell RNA-seq adaptation

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 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 ...
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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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 ; 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 : 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 : 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
Marjolein Schluck1,2, Roel Hammink1,2, Carl G. Figdor1,2,3, Martijn Verdoes1,3*† and Jorieke Weiden1,2,3*† 1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands 2Division of Immunotherapy, Oncode Institute, Radboud University Medical Center, Nijmegen, Netherlands 3Institute for Chemical Immunology, Nijmegen, Netherlands Traditional tumor vaccination approaches mostly focus on activating dendritic cells (DCs) by providing them with a source of tumor antigens and/or adjuvants, which in turn activate tumor-reactive T c...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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