{"doi":"10.7150/thno.100295","title":"CRISPR screening reveals ZNF217 as a vulnerability in high-risk B-cell acute lymphoblastic leukemia","abstract":"Rationale: Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate.Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%.The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses.This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL.Methods: The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth.Both in vitro and in vivo models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL.To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation.Results: Through the focused CRISPR-Cas9 screening, ZNF217 emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL.Through in vitro gain-and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth.Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that ZNF217 depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice.Through integrative multiple-omics analysis, we elucidated that ZNF217 exerts its oncogenic role in B-ALL through both CoREST-dependent and CoREST-independent mechanisms.Furthermore, we characterized FOS as a functionally essential downstream target of ZNF217, and ZNF217 inhibited FOS expression in a CoREST-independent manner.Conclusions: Our findings highlight ZNF217 as a promising therapeutic target for the treatment of high-risk B-ALL, such as those carrying MLL-rearrangements or BCR-ABL fusion.","journal":"Theranostics","year":2025,"id":529968,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":840086,"name":"Keren Zhou","orcid":"0000-0001-7905-3399","position":1,"is_corresponding":false},{"id":87801,"name":"Lei 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Qing","orcid":"0000-0001-6763-6204","position":11,"is_corresponding":false},{"id":635148,"name":"Meiling Chen","orcid":"0000-0002-1589-1710","position":12,"is_corresponding":false},{"id":968721,"name":"Kitty Wang","orcid":"0000-0002-3375-7398","position":13,"is_corresponding":false},{"id":1038050,"name":"Keith Sai Kit Leung","orcid":"0000-0002-4232-763X","position":14,"is_corresponding":false},{"id":1107828,"name":"Lillian Sau","orcid":"0000-0001-8649-6681","position":15,"is_corresponding":false},{"id":1158752,"name":"Chun-Wei Chen","orcid":"0000-0001-6761-3002","position":16,"is_corresponding":false},{"id":87800,"name":"Xiaolan Deng","orcid":"0000-0003-3695-0203","position":17,"is_corresponding":false},{"id":87799,"name":"Rui Su","orcid":"0000-0002-4807-6229","position":18,"is_corresponding":false},{"id":106277,"name":"Jianjun Chen","orcid":"0000-0003-3749-2902","position":19,"is_corresponding":false},{"id":87791,"name":"Xi Qin","orcid":"0000-0002-1154-5634","position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":null,"created_at":"2026-07-19T02:51:01.235017Z","pmid":"40093906","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":[]}