{"doi":"10.1101/2020.05.29.120857","title":"Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter","abstract":"Summary paragraph The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of the hematopoietic master regulator PU.1 1–4 . PU.1 gene expression is regulated through enhancer-promoter interactions within a topologically associated domain (TAD) 5,6 . PU.1 levels increase during myeloid differentiation while failure to do so results in myeloid leukemia 7 . In contrast, T-cell differentiation requires PU.1 to be completely switched off 8–10 . Little is known about the precise mechanisms of PU.1 repression, physiological as in T-cell differentiation, or pathological as in leukemia. Here we demonstrate that the down-regulation of PU.1 mRNA is a dynamic process involving an alternative promoter 11 in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core binding factor (CBF) fusions, RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) acute myeloid leukemia (AML) 12 , activate the PU.1 antisense promoter, thus shifting from sense towards antisense transcription and blocking myeloid differentiation. In patients with CBF-AML, we found that an elevated antisense/sense ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of the enhancer with the proximal or the antisense promoter are at the heart of differential PU.1 expression during myeloid and T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense PU.1 transcription. Our results identify the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. This novel basic disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123730,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567950,"name":"G. Heller","orcid":null,"position":1,"is_corresponding":false},{"id":567951,"name":"A. Czibere","orcid":null,"position":2,"is_corresponding":false},{"id":567952,"name":"L.H. Castilla","orcid":null,"position":3,"is_corresponding":false},{"id":567953,"name":"R. Delwel","orcid":null,"position":4,"is_corresponding":false},{"id":567954,"name":"A. Di Ruscio","orcid":null,"position":5,"is_corresponding":false},{"id":567955,"name":"A.K. Ebralidze","orcid":null,"position":6,"is_corresponding":false},{"id":212375,"name":"M. Forte","orcid":null,"position":7,"is_corresponding":false},{"id":567956,"name":"L. Kazianka","orcid":null,"position":8,"is_corresponding":false},{"id":567957,"name":"C. Kornauth","orcid":null,"position":9,"is_corresponding":false},{"id":567958,"name":"T. Le","orcid":null,"position":10,"is_corresponding":false},{"id":567959,"name":"K. Lind","orcid":null,"position":11,"is_corresponding":false},{"id":567960,"name":"I.A. Monteiro Barbosa","orcid":null,"position":12,"is_corresponding":false},{"id":567961,"name":"A. Pichler","orcid":null,"position":13,"is_corresponding":false},{"id":567962,"name":"J.A. Pulikkan","orcid":null,"position":14,"is_corresponding":false},{"id":567963,"name":"A-S Schmolke","orcid":null,"position":15,"is_corresponding":false},{"id":567964,"name":"H. Sill","orcid":null,"position":16,"is_corresponding":false},{"id":567965,"name":"W.R. Sperr","orcid":null,"position":17,"is_corresponding":false},{"id":567966,"name":"A. Spittler","orcid":null,"position":18,"is_corresponding":false},{"id":567967,"name":"B. Q. Trinh","orcid":null,"position":19,"is_corresponding":false},{"id":567968,"name":"P. Valent","orcid":null,"position":20,"is_corresponding":false},{"id":567969,"name":"K. Vanura","orcid":null,"position":21,"is_corresponding":false},{"id":567970,"name":"R.S. Welner","orcid":null,"position":22,"is_corresponding":false},{"id":567971,"name":"J. Zuber","orcid":null,"position":23,"is_corresponding":false},{"id":567972,"name":"D.G. Tenen","orcid":null,"position":24,"is_corresponding":false},{"id":567973,"name":"P.B. Staber","orcid":null,"position":25,"is_corresponding":false},{"id":567949,"name":"E. van der Kouwe","orcid":null,"position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","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":[]}