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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:p>\n                    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&amp;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 \u201copen\u201d prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin \u201cpioneering factor\u201d 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\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    ,\n                    <jats:italic>Gata2<\/jats:italic>\n                    overexpression induces many of the same epigenetic and transcriptional changes as\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    . These findings suggested that\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    may indirectly initiate its transcriptional program by activating\n                    <jats:italic>Gata2<\/jats:italic>\n                    expression: Indeed, we demonstrated that inactivation of\n                    <jats:italic>Gata2<\/jats:italic>\n                    prior to\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    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\n                    <jats:italic>Gata2<\/jats:italic>\n                    expression.\n                    <jats:italic>Gata2<\/jats:italic>\n                    may therefore be required for\n                    <jats:italic>PML::RARA<\/jats:italic>\n                    to establish its transcriptional program.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2317690121","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T15:06:28Z","timestamp":1713798388000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells"],"prefix":"10.1073","volume":"121","author":[{"given":"Casey D. S.","family":"Katerndahl","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia R. S.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan B.","family":"Day","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-9407","authenticated-orcid":false,"given":"Nichole M.","family":"Helton","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Mukund","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-0520","authenticated-orcid":false,"given":"Timothy J.","family":"Ley","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90112-C"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90113-D"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.8.2826.bloodjournal8882826"},{"key":"e_1_3_4_4_2","first-page":"2945","article-title":"Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: Possible role of the proteasome pathway","volume":"56","author":"Yoshida H.","year":"1996","unstructured":"H. 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