Acute myeloid leukemia (AML) is a genetic disease whereby sequential genetic
aberrations alter essential white blood cell development leading to differentiation arrest
and hyperproliferation. Pertinent animal models serve as essential intermediaries between
in vitro molecular studies and the use of new agents in clinical trials. We previously
generated a transgenic zebrafish model expressing human NUP98-HOXA9 (NHA9), a
fusion oncogene found in high-risk AML. This expression yields a pre-leukemic state in
both embryos and adults. Using this model, we have identified the overexpression of
dnmt1 and the Wnt/β-catenin pathway as downstream contributors to the
myeloproliferative phenotype. Targeted dnmt1 morpholino knockdown and
pharmacological inhibition with methyltransferase inhibitors rescues NHA9 embryos.
Similarly, inhibition of β-catenin with COX inhibitors partially restores normal
hematopoiesis. Interestingly, concurrent treatment with a histone deacetylase inhibitor
and either a methyltransferase inhibitor or a COX inhibitor, synergistically inhibits the
effects of NHA9 on embryonic hematopoiesis. Thus, we have identified potential
pharmacological targets in NHA9-induced myeloid disease that may offer a highly
efficient therapy with limited toxicity – addressing a major long-term goal of AML
research.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:NSHD.ca#10222/36250 |
| Date | 25 July 2013 |
| Creators | Deveau, Adam |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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