{"doi":"10.1101/2024.03.12.584622","title":"Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma","abstract":"Abstract The MYC proto-oncogenes (c-MYC, MYCN , MYCL ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN -amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC–driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine β-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1 + somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of δ cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC–overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":490306,"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":0.949,"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":54940,"name":"Lingling Liu","orcid":"0000-0002-1922-7120","position":1,"is_corresponding":false},{"id":567409,"name":"Jie Fang","orcid":"0000-0001-6119-1195","position":2,"is_corresponding":false},{"id":55234,"name":"Hongjian Jin","orcid":"0000-0003-3833-7170","position":3,"is_corresponding":false},{"id":285758,"name":"Sivaraman Natarajan","orcid":"0000-0003-2608-2887","position":4,"is_corresponding":false},{"id":55235,"name":"Heather Sheppard","orcid":"0000-0002-9623-2812","position":5,"is_corresponding":false},{"id":377548,"name":"Meifen Lu","orcid":null,"position":6,"is_corresponding":false},{"id":1335450,"name":"Gregory Turner","orcid":"0000-0002-9659-8291","position":7,"is_corresponding":false},{"id":1173447,"name":"Thomas Confer","orcid":"0000-0002-1733-0116","position":8,"is_corresponding":false},{"id":370041,"name":"Melissa Johnson","orcid":"0000-0002-3794-3518","position":9,"is_corresponding":false},{"id":1258488,"name":"Jeffrey Steinberg","orcid":"0000-0003-4110-3586","position":10,"is_corresponding":false},{"id":1335681,"name":"Larry Ha","orcid":null,"position":11,"is_corresponding":false},{"id":1222518,"name":"Nour Yadak","orcid":null,"position":12,"is_corresponding":false},{"id":1335682,"name":"Richa Jain","orcid":null,"position":13,"is_corresponding":false},{"id":1145880,"name":"David J. Picketts","orcid":"0000-0002-9227-2016","position":14,"is_corresponding":false},{"id":252138,"name":"Xiaotu Ma","orcid":"0000-0002-6233-2145","position":15,"is_corresponding":false},{"id":381384,"name":"Andrew J. Murphy","orcid":"0000-0001-6747-0355","position":16,"is_corresponding":false},{"id":356186,"name":"Andrew M. Davidoff","orcid":"0000-0001-7900-2794","position":17,"is_corresponding":false},{"id":504802,"name":"Evan S. Glazer","orcid":"0000-0002-5796-0542","position":18,"is_corresponding":false},{"id":5544,"name":"John Easton","orcid":"0000-0003-4503-6608","position":19,"is_corresponding":false},{"id":241111,"name":"Xiang Chen","orcid":"0000-0002-2499-8261","position":20,"is_corresponding":false},{"id":232998,"name":"Ruoning Wang","orcid":"0000-0001-9798-8032","position":21,"is_corresponding":false},{"id":107683,"name":"Jun J. Yang","orcid":"0000-0002-0770-9659","position":22,"is_corresponding":false},{"id":232984,"name":"Tingting Wang","orcid":"0000-0002-6649-3114","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T02:08:32.775003Z","pmid":"38559042","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":[]}