{"doi":"10.1038/s41408-024-00981-4","title":"Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM)","abstract":"Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.","journal":"Blood Cancer Journal","year":2024,"id":464744,"datarank":0.28730158176743725,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.04588589490232218,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.04588589490232218,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"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":304991,"name":"Warren Fiskus","orcid":"0000-0002-7343-6214","position":1,"is_corresponding":false},{"id":109577,"name":"Courtney D. DiNardo","orcid":"0000-0001-9003-0390","position":2,"is_corresponding":false},{"id":567734,"name":"Patrick K. Reville","orcid":"0000-0001-8433-3360","position":3,"is_corresponding":false},{"id":607910,"name":"John A. Davis","orcid":"0000-0002-5809-5976","position":4,"is_corresponding":false},{"id":572008,"name":"Christine Birdwell","orcid":null,"position":5,"is_corresponding":false},{"id":830262,"name":"Kaberi Das","orcid":"0000-0003-4702-0386","position":6,"is_corresponding":false},{"id":404106,"name":"Hanxi Hou","orcid":"0000-0002-1951-3522","position":7,"is_corresponding":false},{"id":108815,"name":"Koichi Takahashi","orcid":"0000-0002-8027-9659","position":8,"is_corresponding":false},{"id":1208601,"name":"Lauren B. Flores","orcid":"0009-0009-5611-6014","position":9,"is_corresponding":false},{"id":1028373,"name":"Xinjia Ruan","orcid":"0000-0003-2309-2641","position":10,"is_corresponding":false},{"id":14097,"name":"Xiaoping Su","orcid":"0000-0003-1824-943X","position":11,"is_corresponding":false},{"id":109581,"name":"Sanam Loghavi","orcid":"0000-0001-8980-3202","position":12,"is_corresponding":false},{"id":304997,"name":"Joseph D. Khoury","orcid":"0000-0003-2621-3584","position":13,"is_corresponding":false},{"id":230407,"name":"Kapil N. Bhalla","orcid":"0000-0001-5209-5126","position":14,"is_corresponding":false},{"id":304992,"name":"Christopher P. Mill","orcid":"0000-0003-0957-6009","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:04:42.082401Z","pmid":"38316746","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":[]}