{"doi":"10.1016/j.ccell.2024.03.003","title":"Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia","abstract":"Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.","journal":"Cancer Cell","year":2024,"id":420232,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8648,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":917358,"name":"Yizhen Li","orcid":"0000-0001-8941-6691","position":1,"is_corresponding":false},{"id":627438,"name":"Jingliao Zhang","orcid":"0000-0003-2962-9884","position":2,"is_corresponding":false},{"id":1043004,"name":"Lei Yan","orcid":"0000-0001-5259-3379","position":3,"is_corresponding":false},{"id":1211094,"name":"Huanbin Zhao","orcid":"0009-0001-4418-6770","position":4,"is_corresponding":false},{"id":351845,"name":"Liang Ding","orcid":"0000-0002-1043-0923","position":5,"is_corresponding":false},{"id":1202451,"name":"Sheetal Bhatara","orcid":"0009-0007-3597-6870","position":6,"is_corresponding":false},{"id":16871,"name":"Yang Xu","orcid":"0000-0003-3898-022X","position":7,"is_corresponding":false},{"id":328020,"name":"Satoshi Yoshimura","orcid":"0000-0002-4756-8790","position":8,"is_corresponding":false},{"id":262379,"name":"Wenjian Yang","orcid":"0000-0002-7305-5649","position":9,"is_corresponding":false},{"id":254764,"name":"Seth E. Karol","orcid":"0000-0001-8113-8180","position":10,"is_corresponding":false},{"id":285762,"name":"Hiroto Inaba","orcid":"0000-0003-0605-7342","position":11,"is_corresponding":false},{"id":247450,"name":"Charles G. Mullighan","orcid":"0000-0002-1871-1850","position":12,"is_corresponding":false},{"id":284142,"name":"Mark R. Litzow","orcid":"0000-0002-9816-6302","position":13,"is_corresponding":false},{"id":262725,"name":"Xiaofan Zhu","orcid":"0000-0002-2572-6495","position":14,"is_corresponding":false},{"id":320821,"name":"Yingchi Zhang","orcid":"0000-0003-1429-0152","position":15,"is_corresponding":false},{"id":230930,"name":"Wendy Stock","orcid":"0000-0002-8349-9200","position":16,"is_corresponding":false},{"id":232850,"name":"Nitin Jain","orcid":"0000-0003-0114-8384","position":17,"is_corresponding":false},{"id":230404,"name":"Elias Jabbour","orcid":"0000-0003-4465-6119","position":18,"is_corresponding":false},{"id":109590,"name":"Steven M. Kornblau","orcid":"0000-0002-5990-9548","position":19,"is_corresponding":false},{"id":18373,"name":"Marina Konopleva","orcid":"0000-0002-9347-2212","position":20,"is_corresponding":false},{"id":254773,"name":"Ching‐Hon Pui","orcid":"0000-0003-0303-5658","position":21,"is_corresponding":false},{"id":241452,"name":"Elisabeth Paietta","orcid":"0000-0002-0561-5544","position":22,"is_corresponding":false},{"id":258247,"name":"William E. Evans","orcid":"0000-0002-9333-5322","position":23,"is_corresponding":false},{"id":55257,"name":"Jiyang Yu","orcid":"0000-0003-1244-4429","position":24,"is_corresponding":false},{"id":107683,"name":"Jun J. 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