An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML
| العنوان: | An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML |
|---|---|
| المؤلفون: | Joseph D. Mancias, Amanda L. Robichaud, Jerome Tamburini, Clément Larrue, Federica Piccioni, Lynn Lee, Anthony Letai, Jeremy Ryan, Shan Lin, Amy Saur Conway, Nastassja K. Scheidegger, Mark Wunderlich, Scott T. Younger, Biniam Adane, Sarah Mouche, Neekesh V. Dharia, Guillaume Kugener, Bo Kyung A. Seong, Thelma Mashaka, Kimberly Stegmaier, Miljan Kuljanin, Caroline Wechsler |
| المساهمون: | University of Zurich, Stegmaier, Kimberly |
| المصدر: | Cancer Discov |
| بيانات النشر: | American Association for Cancer Research, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cell, 610 Medicine & health, Antineoplastic Agents, Computational biology, Article, chemistry.chemical_compound, Genome editing, In vivo, hemic and lymphatic diseases, medicine, CRISPR, Animals, Humans, Precision Medicine, neoplasms, Venetoclax, business.industry, Myeloid leukemia, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, chemistry, 10036 Medical Clinic, 2730 Oncology, CRISPR-Cas Systems, business, Genetic screen |
| الوصف: | CRISPR–Cas9-based genetic screens have successfully identified cell type–dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. Significance: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities. This article is highlighted in the In This Issue feature, p. 275 |
| وصف الملف: | 432.pdf - application/pdf; nihms_1742496.pdf - application/pdf |
| DOI: | 10.5167/uzh-224559 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1c56bc6680b50eddcd2ed9826b4c7ab |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f1c56bc6680b50eddcd2ed9826b4c7ab |
| قاعدة البيانات: | OpenAIRE |
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