Data from An <i>In Vivo</i> CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML

Abstract

<div>Abstract<p>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 <i>in vitro</i> 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 <i>in vivo</i>, 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 <i>SLC5A3</i> as a metabolic vulnerability for AML addicted to exogenous myo-inositol and <i>MARCH5</i> 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 <i>MARCH5</i> in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.</p>Significance:<p>There is an unmet need to improve the clinical outcome of AML. We developed an integrated <i>in vivo</i> screening approach to prioritize and validate AML dependencies with high translational potential. We identified <i>SLC5A3</i> as a metabolic vulnerability and <i>MARCH5</i> as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-2-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 275</a></i></p></div>