{"doi":"10.1073/pnas.2317690121","title":"PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells","abstract":"The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are “open” prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin “pioneering factor” GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA , Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA . These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":446657,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"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":1264322,"name":"Olivia R. S. Rogers","orcid":null,"position":1,"is_corresponding":false},{"id":846600,"name":"Ryan B. Day","orcid":"0000-0002-4376-4663","position":2,"is_corresponding":false},{"id":1094929,"name":"Ziheng Xu","orcid":"0000-0001-6303-5823","position":3,"is_corresponding":false},{"id":665040,"name":"Nichole Helton","orcid":"0000-0001-8308-9407","position":4,"is_corresponding":false},{"id":353509,"name":"Sai Mukund Ramakrishnan","orcid":"0000-0002-4500-6583","position":5,"is_corresponding":false},{"id":13814,"name":"Christopher A. Miller","orcid":"0000-0003-4266-6700","position":6,"is_corresponding":false},{"id":18438,"name":"Timothy J. Ley","orcid":"0000-0002-9913-0520","position":7,"is_corresponding":false},{"id":789042,"name":"Casey Katerndahl","orcid":"0000-0002-7522-1946","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T02:01:54.980444Z","pmid":"38648485","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":[]}