Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease

Deveau, A.P., Forrester, A.M., Coombs, A.J., Wagner, G.S., Grabher, C., Chute, I.C., Léger, D., Mingay, M., Alexe, G., Rajan, V., Liwski, R., Hirst, M., Steigmaier, K., Lewis, S.M., Look, A.T., Berman, J.N.
Leukemia   29(10): 2086-97 (Journal)
Registered Authors
Berman, Jason, Coombs, Andrew, Deveau, Adam, Forrester, Michael, Grabher, Clemens, Look, A. Thomas, Rajan, Vinothkumar
MeSH Terms
  • Adult
  • Animals
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/metabolism
  • Biomarkers, Tumor/antagonists & inhibitors
  • Biomarkers, Tumor/genetics
  • Biomarkers, Tumor/metabolism
  • Cell Transformation, Neoplastic/drug effects
  • Cell Transformation, Neoplastic/metabolism
  • Cell Transformation, Neoplastic/pathology
  • Cells, Cultured
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/drug effects*
  • Embryo, Nonmammalian/metabolism
  • Epigenesis, Genetic/drug effects*
  • Gene Expression Profiling
  • Hematopoiesis/drug effects
  • Hematopoiesis/physiology*
  • Histone Deacetylase Inhibitors/therapeutic use*
  • Homeodomain Proteins/genetics*
  • Humans
  • In Situ Hybridization
  • Leukemia, Myeloid, Acute/etiology
  • Leukemia, Myeloid, Acute/pathology
  • Leukemia, Myeloid, Acute/prevention & control*
  • Myeloproliferative Disorders/etiology
  • Myeloproliferative Disorders/pathology
  • Myeloproliferative Disorders/prevention & control*
  • Nuclear Pore Complex Proteins/genetics*
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins, Fusion/genetics*
  • Phenotype
  • Promoter Regions, Genetic/genetics
  • RNA, Messenger/genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transgenes/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
26017032 Full text @ Leukemia
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 pre-leukemic 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 DNMT inhibitors or cyclo-oxygenase 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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes