التفاصيل البيبلوغرافية
| العنوان: |
Focused CRISPR-Cas9 genetic screening reveals USO1 as a vulnerability in B-cell acute lymphoblastic leukemia |
| المؤلفون: |
Jaiswal, Amit Kumar, Truong, Hellen, Tran, Tiffany M, Lin, Tasha L, Casero, David, Alberti, Michael O, Rao, Dinesh S |
| المصدر: |
Scientific Reports, vol 11, iss 1 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2021 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Biotechnology, Childhood Leukemia, Genetics, Pediatric, Pediatric Cancer, Cancer, Human Genome, Hematology, Pediatric Research Initiative, Aetiology, 2.1 Biological and endogenous factors, Animals, CRISPR-Cas Systems, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Leukemic, Genes, Reporter, Genetic Predisposition to Disease, Genetic Testing, Golgi Matrix Proteins, Homeostasis, Humans, Mice |
| الوصف: |
Post-transcriptional gene regulation, including that by RNA binding proteins (RBPs), has recently been described as an important mechanism in cancer. We had previously identified a set of RBPs that were highly dysregulated in B-cell acute lymphoblastic leukemia (B-ALL) with MLL translocations, which carry a poor prognosis. Here, we sought to functionally characterize these dysregulated RBP genes by performing a focused CRISPR dropout screen in B-ALL cell lines, finding dependencies on several genes including EIF3E, EPRS and USO1. Validating our findings, CRISPR/Cas9-mediated disruption of USO1 in MLL-translocated B-ALL cells reduced cell growth, promoted cell death, and altered the cell cycle. Transcriptomic analysis of USO1-deficient cells revealed alterations in pathways related to mTOR signaling, RNA metabolism, and targets of MYC. In addition, USO1-regulated genes from these experimental samples were significantly and concordantly correlated with USO1 expression in primary samples collected from B-ALL patients. Lastly, we found that loss of Uso1 inhibited colony formation of MLL-transformed in primary bone marrow cells from Cas9-EGFP mice. Together, our findings demonstrate an approach to performing focused sub-genomic CRISPR screens and highlight a putative RBP vulnerability in MLL-translocated B-ALL, thus identifying potential therapeutic targets in this disease. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt8wv4467q; https://escholarship.org/uc/item/8wv4467qTest |
| الإتاحة: |
https://escholarship.org/uc/item/8wv4467qTest |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.3C61275E |
| قاعدة البيانات: |
BASE |
