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The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes. In this study we investigated the expression of human MLL-ENL and MLL-AF9 in the myeloid lineage of zebrafish embryos. We observed an expansion of <jats:italic>MLL<\/jats:italic> positive cells and determined these cells colocalized with the myeloid markers <jats:italic>spi1b<\/jats:italic>, <jats:italic>mpx<\/jats:italic>, and <jats:italic>mpeg<\/jats:italic>. In addition, expression of <jats:italic>MLL-ENL<\/jats:italic> and <jats:italic>MLL-AF9<\/jats:italic> induced the expression of endogenous <jats:italic>bcl2<\/jats:italic> and <jats:italic>cdk9<\/jats:italic>, genes that are often dysregulated in MLL-r-AML. Co-treatment of <jats:italic>lyz<\/jats:italic>: <jats:italic>MLL-ENL<\/jats:italic> or <jats:italic>lyz<\/jats:italic>:<jats:italic>MLL-AF9<\/jats:italic> expressing embryos with the BCL2 inhibitor, Venetoclax, and the CDK9 inhibitor, Flavopiridol, significantly reduced the number of <jats:italic>MLL<\/jats:italic> positive cells compared to embryos treated with vehicle or either drug alone. In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous <jats:italic>mcl1a<\/jats:italic> compared to vehicle, consistent with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011308","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T17:40:02Z","timestamp":1717436402000},"page":"e1011308","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4580-6208","authenticated-orcid":true,"given":"Alex J.","family":"Belt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Tombes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3897-2898","authenticated-orcid":true,"given":"Sarah C.","family":"Rothschild","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"issue":"1","key":"pgen.1011308.ref001","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1182\/asheducation-2016.1.348","article-title":"Mutations in AML: prognostic and therapeutic implications","volume":"2016","author":"CD DiNardo","year":"2016","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"pgen.1011308.ref002","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fped.2017.00004","article-title":"MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches","volume":"5","author":"AC Winters","year":"2017","journal-title":"Front Pediatr"},{"issue":"2","key":"pgen.1011308.ref003","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/leu.2017.213","article-title":"The MLL recombinome of acute leukemias in 2017","volume":"32","author":"C Meyer","year":"2018","journal-title":"Leukemia"},{"issue":"40","key":"pgen.1011308.ref004","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1038\/onc.2016.30","article-title":"The molecular mechanics of mixed lineage leukemia","volume":"35","author":"RK Slany","year":"2016","journal-title":"Oncogene"},{"issue":"13","key":"pgen.1011308.ref005","doi-asserted-by":"crossref","first-page":"4445","DOI":"10.1182\/blood-2007-05-090514","article-title":"A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification","volume":"110","author":"D Mueller","year":"2007","journal-title":"Blood"},{"issue":"2","key":"pgen.1011308.ref006","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/dvdy.20516","article-title":"Transposon tools and methods in zebrafish","volume":"234","author":"K. 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