{"doi":"10.1101/2020.12.22.424018","title":"<i>In vivo</i> genetic screen identifies a SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia","abstract":"Abstract An enhanced requirement for extracellular nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy for evaluating dependencies in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a unique vulnerability in this disease. In accord with this transport function, we demonstrate that the SLC5A3 dependency reflects a myo-inositol auxotrophy in AML. Importantly, the commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1 , which encodes the rate limiting enzyme for myoinositol biosynthesis, inositol-3-phosphate synthase 1. We used gain- and loss-of-function experiments to demonstrate a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with the presence of IDH1/IDH2 and CEBPA mutations. Collectively, our findings reveal myo-inositol auxotrophy as a novel form of metabolic dysregulation in AML, which is caused by the aberrant silencing of a biosynthetic enzyme. Statement of significance Here, we show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically-defined subset of AML.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120592,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":558568,"name":"Shruti V. Iyer","orcid":"0000-0002-4351-9975","position":1,"is_corresponding":false},{"id":558569,"name":"Ana S.H. Costa","orcid":"0000-0001-8932-6370","position":2,"is_corresponding":false},{"id":558570,"name":"Zhaolin Yang","orcid":"0000-0002-7857-9724","position":3,"is_corresponding":false},{"id":107893,"name":"Melissa Kramer","orcid":"0000-0001-9669-3611","position":4,"is_corresponding":false},{"id":75038,"name":"Emmalee R. Adelman","orcid":"0000-0003-3429-0803","position":5,"is_corresponding":false},{"id":558571,"name":"Olaf Klingbeil","orcid":"0000-0001-7248-7506","position":6,"is_corresponding":false},{"id":558572,"name":"Osama E. Demerdash","orcid":"0000-0002-9896-2077","position":7,"is_corresponding":false},{"id":558573,"name":"Sofya A. Polyanskaya","orcid":"0000-0003-3664-3967","position":8,"is_corresponding":false},{"id":307832,"name":"Kenneth Chang","orcid":"0000-0002-5833-3655","position":9,"is_corresponding":false},{"id":107894,"name":"Sara Goodwin","orcid":"0000-0002-6110-7296","position":10,"is_corresponding":false},{"id":17369,"name":"Emily Hodges","orcid":"0000-0001-6513-610X","position":11,"is_corresponding":false},{"id":33868,"name":"W. Richard McCombie","orcid":"0000-0003-1899-0682","position":12,"is_corresponding":false},{"id":75044,"name":"Maria E. Figueroa","orcid":"0000-0003-4887-4981","position":13,"is_corresponding":false},{"id":251322,"name":"Christopher R. Vakoc","orcid":"0000-0002-1158-7180","position":14,"is_corresponding":false},{"id":558567,"name":"Yiliang Wei","orcid":"0000-0001-8956-2955","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:14:38.147936Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}