{"doi":"10.1101/2023.03.27.534395","title":"Therapeutic targeting of ACLY in T-ALL <i>in vivo</i>","abstract":"Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as overexpressed and as a novel therapeutic target in T-ALL. To test the effects of ACLY in leukemia progression, we developed an isogenic model of NOTCH1-induced Acly conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition in vivo. Metabolomic profiling upon ACLY loss revealed a metabolic crisis with reduced acetyl-CoA levels, as well as a decreased oxygen consumption rate. Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of MYC loss in vivo . Mechanistically, the decrease in acetyl-CoA led to reduced H3K27ac levels in Myc , resulting in transcriptional downregulation of Myc and drastically reduced MYC protein levels. Interestingly, our analyses also revealed a reciprocal relationship whereby ACLY itself is a direct transcriptional target of MYC, thus establishing a feedforward loop that is important for leukemia progression. Overall, our results identified a relevant ACLY-MYC axis and unveiled ACLY as a novel promising target for T-ALL treatment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":396115,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491647,"name":"Amartya Singh","orcid":"0000-0003-2422-3068","position":1,"is_corresponding":false},{"id":480793,"name":"Maya Aleksandrova","orcid":"0000-0002-7881-9521","position":2,"is_corresponding":false},{"id":1171754,"name":"Oekyung Kim","orcid":null,"position":3,"is_corresponding":false},{"id":1171755,"name":"Christopher Thai","orcid":null,"position":4,"is_corresponding":false},{"id":267436,"name":"Olga Lancho","orcid":"0000-0001-5819-4715","position":5,"is_corresponding":false},{"id":933054,"name":"Patrícia Renck Nunes","orcid":"0000-0002-9680-0779","position":6,"is_corresponding":false},{"id":559464,"name":"Hayley C. Affronti","orcid":"0000-0001-9751-0629","position":7,"is_corresponding":false},{"id":244441,"name":"Xiaoyang Su","orcid":"0000-0001-8081-1396","position":8,"is_corresponding":false},{"id":237766,"name":"Kathryn E. Wellen","orcid":"0000-0002-2281-0042","position":9,"is_corresponding":false},{"id":267441,"name":"Daniel Herranz","orcid":"0000-0003-1768-5969","position":10,"is_corresponding":false},{"id":267438,"name":"Victoria da Silva-Diz","orcid":"0000-0002-1508-2999","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:27.044553Z","pmid":"37034581","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":[]}