SLC5A3 Transports Myo-Inositol to Support the Growth of Acute Myeloid Leukemia

Metabolic reprogramming contributes to tumor development and sustains cancer cell proliferation. Like other cancers, acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival, has altered metabolic features, providing new possibilities for AML treatment. Since the niche can reshape the metabolic properties of cancer cells, it is critical to validate AML metabolic vulnerabilities in a proper microenvironment. To this end, we optimized a protocol for CRISPR screening in orthotopic xenograft AML models, including patient-derived-xenograft (PDX) models tractable for CRISPR-editing, to enable the systematic evaluation of the physiological relevance of top AML dependencies. We performed in vivo screens in MV4-11 and U937 cell lines and a PDX model, which converged to reveal the sodium/myo-inositol cotransporter SLC5A3 as a top-ranked in vivo gene target.