CRISPR-GEMM pooled mutagenic screening identifies KMT2D as a major modulator of immune checkpoint blockade (ATAC-Seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA635151 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11851644_1.fastq.gz | Fastqsanger.gz | |||
| SRR11851644_2.fastq.gz | Fastqsanger.gz | |||
| SRR11851645_1.fastq.gz | Fastqsanger.gz | |||
| SRR11851645_2.fastq.gz | Fastqsanger.gz | |||
| SRR11851646_1.fastq.gz | Fastqsanger.gz |
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Project description:Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy across multiple cancer types. However, only a fraction of patients respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMMs) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. Kmt2d encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in cancer patients. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. Additionally, Kmt2d-deficient cells exhibit increased protein turnover and IFN-γ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human are characterized by increased immune infiltration. These data demonstrate that KMT2D deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, highlighting the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.
2020-11-18 | GSE151226 | GEO
Project description:Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy across multiple cancer types. However, only a fraction of patients respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMMs) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. Kmt2d encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in cancer patients. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. Additionally, Kmt2d-deficient cells exhibit increased protein turnover and IFN-γ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human are characterized by increased immune infiltration. These data demonstrate that KMT2D deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, highlighting the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.
2020-11-18 | GSE151225 | GEO
Project description:CRISPR-GEMM pooled mutagenic screening identifies KMT2D as a major modulator of immune checkpoint blockade
| PRJNA635149 | ENA
Project description:CRISPR-GEMM pooled mutagenic screening identifies KMT2D as a major modulator of immune checkpoint blockade (RNA-Seq)
| PRJNA635150 | ENA
Project description:Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment. SIGNIFICANCE: ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.This article is highlighted in the In This Issue feature, p. 1775.
| S-EPMC7710536 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-11-18 | GSE151227 | GEO
Project description:Somatic mutations in various epigenetic regulators, including histone methyltransferases KMT2C and KMT2D, have emerged as important cancer-driving events. However, the mechanism of action and therapeutic vulnerability imparted by these mutations remain poorly understood. We identified KMT2D and 8 other epigenetic regulators as potential suppressors to melanoma initiation through an in vivo pooled epigenome-focused RNAi screen. Loss of KMT2D, which exhibits somatic mutations in human melanoma and other cancers, drastically enhanced melanoma progression in xenograft models and a BRAFV600E-driven genetically engineered mouse model of melanoma. Epigenome profiling of 6 histone marks and chromatin state alterations showed substantial reprogramming of H3K4me1- and H3K27ac-marked active enhancer states in KMT2D mutant tumors. Energy metabolic pathways such as glycolysis, OxPhos and TCA/electron transport showed high degree of deregulation which was confirmed with metabolic profiling. Pharmacological abrogation of glycolysis led to reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, we find that enhancer loss at IGFBPs increases IGF signaling and downstream AKT phosphorylation that leads to upregulation of metabolic pathways rendering KMT2D mutant cells dependent on these energy metabolism pathways for their higher growth potential. Overall, we present evidence that KMT2D mutations promote tumorigenesis by reprogramming energy metabolism pathways through enhancer reprogramming.
2020-11-16 | GSE116852 | GEO
Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data. Primary tumors from CRC GEMMs with different combinations of mutant alleles of interested were generated and analyzed. Alleles include mutant forms of APC (A), P53 (P), KRAS (K) and BRAF (B).
2014-07-01 | E-GEOD-50794 | biostudies-arrayexpress
Project description:Somatic mutations in various epigenetic regulators, including histone methyltransferases KMT2C and KMT2D, have emerged as important cancer-driving events. However, the mechanism of action and therapeutic vulnerability imparted by these mutations remain poorly understood. We identified KMT2D and 8 other epigenetic regulators as potential suppressors to melanoma initiation through an in vivo pooled epigenome-focused RNAi screen. Loss of KMT2D, which exhibits somatic mutations in human melanoma and other cancers, drastically enhanced melanoma progression in xenograft models and a BRAFV600E-driven genetically engineered mouse model of melanoma. Epigenome profiling of 6 histone marks and chromatin state alterations showed substantial reprogramming of H3K4me1- and H3K27ac-marked active enhancer states in KMT2D mutant tumors. Energy metabolic pathways such as glycolysis, OxPhos and TCA/electron transport showed high degree of deregulation which was confirmed with metabolic profiling. Pharmacological abrogation of glycolysis led to reduced proliferation and tumorigenesis preferentially in KMT2D mutant cells. Mechanistically, we find that enhancer loss at IGFBPs increases IGF signaling and downstream AKT phosphorylation that leads to upregulation of metabolic pathways rendering KMT2D mutant cells dependent on these energy metabolism pathways for their higher growth potential. Overall, we present evidence that KMT2D mutations promote tumorigenesis by reprogramming energy metabolism pathways through enhancer reprogramming.
2020-11-16 | GSE116851 | GEO