Levi D. Ali
A5004652374- CRISPR and Genetic Engineering
- Bioinformatics and Genomic Networks
- Genomics and Chromatin Dynamics
- Pluripotent Stem Cells Research
- Advanced biosensing and bioanalysis techniques
- Mitochondrial Function and Pathology
- Cell Image Analysis Techniques
- Computational Drug Discovery Methods
- Power Systems Fault Detection
- Genetics, Aging, and Longevity in Model Organisms
- Genetics, Bioinformatics, and Biomedical Research
- Molecular Biology Techniques and Applications
- Medical Imaging and Pathology Studies
- Neuroblastoma Research and Treatments
- Cancer Genomics and Diagnostics
- Genetics and Neurodevelopmental Disorders
- Photosynthetic Processes and Mechanisms
- Cancer-related gene regulation
- Nutrition, Genetics, and Disease
- Metabolomics and Mass Spectrometry Studies
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Aortic Thrombus and Embolism
- Health, Environment, Cognitive Aging
- Single-cell and spatial transcriptomics
University of Massachusetts Chan Medical School
2020-2025
Broad Institute
2011-2017
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...
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...
Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood neuroblastoma, amplification of oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening MYCN-amplified neuroblastoma found preferential dependency on genes encoding polycomb repressive complex 2 (PRC2) components EZH2, EED, SUZ12. Genetic pharmacological suppression EZH2 inhibited growth...
The CRISPR-Cas9 system has revolutionized gene editing both on single genes and in multiplexed loss-of-function screens, enabling precise genome-scale identification of essential to proliferation survival cancer cells. However, previous studies reported that an anti-proliferative effect Cas9-mediated DNA cleavage confounds such measurement genetic dependency, particularly the setting copy number gain 1-4 . We performed essentiality screens 342 cell lines found this is common all lines,...
The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP ATFS-1 which promotes homeostasis (proteostasis) and biogenesis in Caenorhabditis elegans . Upon perturbation, ATFS-1-dependent transcriptional program gene expression, leading to recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, short-lived. However, develop adults suggesting presence of other signaling pathways that promote function absence We...
Abstract The mapping of cancer genomes is rapidly approaching completion. genomic information encoded by individual patients' tumors should, in principle, provide a guide for predicting acquired dependencies. Unfortunately, while the success precision genomics hinges on decoding such dependencies, we lack ability to predict dependencies most tumors. challenge stems from absence clinical data relating genotypes with since mutations are rare and our arsenal drugs incomplete. A comprehensive...
Abstract This abstract is being presented as a short talk in the scientific program. A full printed Proffered Abstracts section (PR02) of Conference Proceedings. Citation Format: Aviad Tsherniak, Francisca Vazquez, Barbara Weir, Philip Montgomery, Glenn Cowley, Stanley Gill, Gregory Kryukov, Sasha Pantel, Will Harrington, Mike Burger, Robin Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Garraway, Jesse Boehm, David Root, Todd Golub, William Hahn. Towards Cancer Dependency Map. [abstract]. In:...
<p>Supplementary Methods</p>
<p>Supplementary Figure S6. Representative example of complex amplified locus showing a CRISPR-CN correlation. Supplementary S7. Comparative analysis the relationship CRISPR-Cas9 guide scores to predicted number CRISPR-Cas9-induced DNA cuts based on either copy or total perfect-match on- and off-target alignments. S8. Comprehensive sensitivity correlated conferred by each sgRNA. S9. (A) PANC-1 infection efficiency corresponding 6 in vitro validation experiment measuring short-term...
<p>Supplementary Figure S1. Genome-scale CRISPR-Cas9 screening identifies a strong correlation between copy number and sensitivity to genome editing. Supplementary S2. Global summary of the relationship guide scores genomic for all 33 cell lines screened. S3. Amplified genes represent strongest perceived dependencies in pooled data. S4. Evaluation influence on dependency published data from Hart et al. (25). S5. Representative examples structural variations leading amplification...
<p>Supplementary Figure Legends</p>