{"doi":"10.1101/2021.01.06.425608","title":"Network Analysis Reveals Synergistic Genetic Dependencies for Rational Combination Therapy in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia","abstract":"ABSTRACT Systems biology approaches can identify critical targets in complex cancer signaling networks to inform therapy combinations and overcome conventional treatment resistance. Herein, we developed a data-driven, network controllability-based approach to identify synergistic key regulator targets in Philadelphia chromosome-like B-acute lymphoblastic leukemia (Ph-like B-ALL), a high-risk leukemia subtype associated with hyperactive signal transduction and chemoresistance. Integrated analysis of 1,046 childhood B-ALL cases identified 14 dysregulated network nodes in Ph-like ALL involved in aberrant JAK/STAT, Ras/MAPK, and apoptosis pathways and other critical processes. Consistent with network controllability theory, combination small molecule inhibitor therapy targeting a pair of key nodes shifted the transcriptomic state of Ph-like ALL cells to become less like kinase-activated BCR-ABL1 -rearranged (Ph+) B-ALL and more similar to prognostically-favorable childhood B-ALL subtypes. Functional validation experiments further demonstrated enhanced anti-leukemia efficacy of combining the BCL-2 inhibitor venetoclax with tyrosine kinase inhibitors ruxolitinib or dasatinib in vitro in human Ph-like ALL cell lines and in vivo in multiple patient-derived xenograft models. Our study represents a broadly-applicable conceptual framework for combinatorial drug discovery, based on systematic interrogation of synergistic vulnerability pathways with pharmacologic targeted validation in sophisticated preclinical human leukemia models.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":220044,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":777149,"name":"Hannah Kim","orcid":"0000-0002-6366-1741","position":1,"is_corresponding":false},{"id":819675,"name":"Kellyn Madden","orcid":null,"position":2,"is_corresponding":false},{"id":324652,"name":"Joseph P. Loftus","orcid":null,"position":3,"is_corresponding":false},{"id":496140,"name":"Gregory M. Chen","orcid":"0000-0002-4083-5083","position":4,"is_corresponding":false},{"id":819676,"name":"David Hottman Allen","orcid":null,"position":5,"is_corresponding":false},{"id":790221,"name":"Ruitao Zhang","orcid":"0000-0001-5610-9433","position":6,"is_corresponding":false},{"id":497397,"name":"Jason Xu","orcid":"0000-0001-5472-3720","position":7,"is_corresponding":false},{"id":819235,"name":"Yuxuan Hu","orcid":"0000-0002-8830-6893","position":8,"is_corresponding":false},{"id":273631,"name":"Sarah K. Tasian","orcid":"0000-0003-1327-1662","position":9,"is_corresponding":false},{"id":225110,"name":"Kai Tan","orcid":"0000-0002-9104-5567","position":10,"is_corresponding":false},{"id":496141,"name":"Yangyang Ding","orcid":"0000-0003-1588-2571","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T23:53:42.928212Z","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":[]}