USING A TRANSGENIC ZEBRAFISH MODEL TO IDENTIFY DOWNSTREAM THERAPEUTIC TARGETS IN HIGH-RISK, NUP98-HOXA9-INDUCED MYELOID DISEASE

Abstract

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.