title: Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease.
abstract: Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98-HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5)-methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds.
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Deveau
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Forrester
authors.affiliation: Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.|Department of Marine Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Coombs
authors.affiliation: Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.|Department of Marine Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: G S
authors.initials: GS
authors.lastname: Wagner
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Institute of Toxicology & Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Grabher
authors.affiliation: Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada.
authors.forename: I C
authors.initials: IC
authors.lastname: Chute
authors.affiliation: Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Léger
authors.affiliation: Department of Microbiology & Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Mingay
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Alexe
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Rajan
authors.affiliation: Department of Pathology, Queen Elizabeth II Health Science Centre, Halifax, Nova Scotia, Canada.|Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Liwski
authors.affiliation: Department of Microbiology & Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Steigmaier
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada.|Department of Chemistry & Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada.|Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada.|Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: J N
authors.initials: JN
authors.lastname: Berman
mesh_terms: D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C400441:NUP98-HOXA9 fusion protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D029961:Zebrafish Proteins