An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 16, 2021
- Source ID
- 10.1158/2159-8290.cd-20-1851
Entities
People
- Amanda L. Robichaud
- Amy Saur Conway
- Anthony Letai
- Biniam Adane
- Bo Kyung A. Seong
- Caroline S. Wechsler
- Clément Larrue
- Federica Piccioni
- Guillaume Kugener
- Jeremy Ryan
- Joseph D Mancias
- Jérôme Tamburini
- Kimberly Stegmaier
- Lynn Lee
- Mark Wunderlich
- Miljan Kuljanin
- Nastassja K. Scheidegger
- Neekesh Dharia
- Sarah Mouche
- Scott T. Younger
- Shan Lin
- Thelma Mashaka
Organizations
- Cincinnati Children's Hospital Medical Center
- Dana–Farber Cancer Institute
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Cincinnati
- University of Geneva