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Animal Models

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

Leukemia volume 29, pages 2086–2097 (2015)Cite this article

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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.

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Acknowledgements

We thank Angela Young, Jessica Hill and Emma Cummings for zebrafish care and maintenance; Jocelyn Jaques for administrative support. This work is supported by a Canadian Institutes of Health Research /Nova Scotia Health Research Foundation Regional Partnership Program Grant MED-Matching 2011–7509 (CIHR#.243778). APD is funded by The Cancer Research Training Program, supported by The Terry Fox Strategic Health Research Training Program in Cancer Research by the Beatrice Hunter Cancer Research Institute. AMF is funded by a Canadian Institutes of Health Research Banting and Best Graduate Student Award. The MeDIP work is supported by the MeDIP-seq Program Project Grant funded by Terry Fox Foundation (TFF-122869) to MH. JNB is supported by a Cancer Care Nova Scotia Peggy Davison Clinician Scientist Award.

Author contributions

APD and AMF conceived and conducted experiments, analyzed the data and wrote the paper. AJC and GSW conducted experiments and analyzed the data. CG generated the original NUP98-HOXA9 transgenic zebrafish line. ICC and DL performed microarray experiments and analyzed microarray data. MM performed MeDIP studies and analyzed methylation data. GA conducted human AML gene data set analysis. VR generated associated microarray figures. RL performed cytospins and cell morphological analysis. MH oversaw MeDIP studies and analysis and edited the manuscript. SML oversaw microarray studies and analysis and edited the manuscript. KS oversaw human AML gene data set analysis. ATL oversaw development of original NUP98–HOXA9-transgenic line and edited the manuscript. JNB conceived experiments, oversaw all the zebrafish studies, wrote and edited the manuscript.

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Author notes

  1. A P Deveau and A M Forrester: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

    A P Deveau, A M Forrester, V Rajan, S M Lewis & J N Berman

  2. Department of Pediatrics, IWK Health Centre, Halifax, Nova Scotia, Canada

    A P Deveau, A M Forrester, A J Coombs, G S Wagner, V Rajan & J N Berman

  3. Department of Marine Biology, Dalhousie University, Halifax, Nova Scotia, Canada

    A J Coombs & G S Wagner

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    C Grabher, G Alexe, K Stegmaier & A T Look

  5. Institute of Toxicology & Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany

    C Grabher

  6. Department of Biology, University of New Brunswick, Saint John, New Brunswick, Canada

    I C Chute, D Léger & S M Lewis

  7. Department of Microbiology & Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada

    M Mingay & M Hirst

  8. Harvard Medical School, Boston, MA, USA

    G Alexe & K Stegmaier

  9. Department of Pathology, Queen Elizabeth II Health Science Centre, Halifax, Nova Scotia, Canada

    R Liwski

  10. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

    R Liwski & J N Berman

  11. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada

    M Hirst

  12. Department of Chemistry & Biochemistry, Université de Moncton, Moncton, New Brunswick, Canada

    S M Lewis

  13. Atlantic Cancer Research Institute, Moncton, New Brunswick, Canada

    S M Lewis

  14. Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

    J N Berman

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  1. A P Deveau
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  2. A M Forrester
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  3. A J Coombs
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Deveau, A., Forrester, A., Coombs, A. et al. Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98–HOXA9-induced myeloid disease. Leukemia 29, 2086–2097 (2015). https://doi.org/10.1038/leu.2015.126

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