A5060190177- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Lung Cancer Treatments and Mutations
- Cancer-related gene regulation
- Sarcoma Diagnosis and Treatment
- Microtubule and mitosis dynamics
- Melanoma and MAPK Pathways
- Ferroptosis and cancer prognosis
- CAR-T cell therapy research
- Computational Drug Discovery Methods
- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Cancer, Hypoxia, and Metabolism
- Advanced biosensing and bioanalysis techniques
- Cholangiocarcinoma and Gallbladder Cancer Studies
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Molecular Biology Techniques and Applications
- PARP inhibition in cancer therapy
Janssen (United States)
2017-2025
Broad Institute
2014-2024
Janssen (Belgium)
2023
Springhouse
2022-2023
Harvard University
1992-2022
Massachusetts Institute of Technology
2012-2022
Massachusetts General Hospital
1997-2013
Dana-Farber Cancer Institute
2012-2013
Beth Israel Deaconess Medical Center
2013
Dana-Farber/Harvard Cancer Center
2013
Focusing on the Right Metabolite A variety of human cancers, including acute leukemias and brain tumors, have mutations in genes encoding isocitrate dehydrogenase 1 or 2 (IDH1, IDH2), which cause overproduction a metabolite called 2-hydroxyglutarate (2HG). Losman et al. (p. 1621 , published online 7 February) show that R - but not S -enantiomer 2HG can transform cells -2HG mediates transformation at least part through effects protein modifying EglN prolyl hydroxylases. Importantly,...
The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function 33 cancer lines to identify genes essential for proliferation/survival found a strong correlation between increased gene copy number decreased viability after editing. Within regions of copy-number gain, targeting both expressed unexpressed genes, as well intergenic loci, led significantly proliferation through induction G2 cell-cycle arrest. By...
The discovery of cancer dependencies has the potential to inform therapeutic strategies and identify putative drug targets. Integrating data from comprehensive genomic profiling cell lines functional characterization dependencies, we discovered that loss enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) its binding partner WDR77. MTAP is frequently lost due proximity commonly deleted tumor suppressor gene, CDKN2A....
Night blindness is an early symptom of retinitis pigmentosa. The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment.
Significance We present, to our knowledge, the first comprehensive next-generation sequencing of osteosarcoma in combination with a functional genomic screen genetically defined mouse model osteosarcoma. Our data provide strong rationale for targeting phosphatidylinositol 3-kinase/mammalian target rapamycin pathway and foundation rational clinical trial design. These findings present an immediate opportunity because multiple inhibitors this are currently trials.
A comprehensive understanding of the molecular vulnerabilities every type cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project identify genes with aberrant copy number, sequence, or expression in various types, providing survey that may have causal role cancer. complementary approach is perform systematic loss-of-function studies essential particular cell types. We begun effort, termed Achilles, aimed at identifying genetic...
Abstract Using a genome-scale, lentivirally delivered shRNA library, we performed massively parallel pooled screens in 216 cancer cell lines to identify genes that are required for proliferation and/or viability. Cell line dependencies on 11,000 were interrogated by 5 shRNAs per gene. The effect of each was assessed transducing population 11M cells with one shRNA-virus and determining the relative enrichment or depletion 54,000 after 16 doublings using Next Generation Sequencing. All...
The Holt-Oram syndrome is an autosomal dominant condition characterized by skeletal abnormalities that are frequently accompanied congenital cardiac defects. cause of these disparate clinical features unknown. To identify the chromosomal location gene, we performed and genetic studies.
We searched for point mutations in every exon of the rhodopsin gene 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including 4 we reported previously, found a total 17 different that correlate disease. Each these is single-base substitution corresponding to single amino acid substitution. Based on current models structure rhodopsin, 3 mutant acids are normally located cytoplasmic side protein, 6 transmembrane domains, and 8 intradiscal side. Forty-three...
RAF inhibitors such as vemurafenib and dabrafenib block BRAF-mediated cell proliferation achieve meaningful clinical benefit in the vast majority of patients with BRAF(V600E)-mutant melanoma. However, some do not respond to this regimen, nearly all progress therapeutic resistance. We used a pooled RNA interference screen targeting more than 16,500 genes discover loss-of-function events that could drive resistance inhibition. The highest ranking gene was NF1, which encodes neurofibromin,...
Ovarian cancer is the most lethal of all gynecological cancers, and there an urgent unmet need to develop new therapies. Epithelial ovarian (EOC) characterized by immune suppressive microenvironment, response cancers therapies has thus far been disappointing. We now find, in a mouse model EOC, that clinically relevant doses DNA methyltransferase histone deacetylase inhibitors (DNMTi HDACi, respectively) reduce microenvironment through type I IFN signaling improve checkpoint therapy. These...
The neurofibromatosis type 1 (NF1) tumor suppressor protein is thought to restrict cell proliferation by functioning as a Ras-specific guanosine triphosphatase–activating protein. However, Drosophila homozygous for null mutations of an NF1 homolog showed no obvious signs perturbed Ras1-mediated signaling. Loss resulted in reduction size larvae, pupae, and adults. This defect was not modified manipulating Ras1 signaling but restored expression activated adenosine 3′,5′-monophosphate–dependent...