Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease
Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease
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DOI：
10.1038/leu.2015.126
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发表时间：
2015-10-01
期刊：
影响因子：
11.4
通讯作者：
Berman, J. N.
中科院分区：
文献类型：
--
作者：
Deveau, A. P.;Forrester, A. M.;Berman, J. N.
急性髓性白血病（AML）发生时，多种遗传畸变改变白色血细胞的发展，导致过度增殖和细胞分化的停滞。相关的动物模型将体外研究与临床试验中使用的新药联系起来。我们产生了一种表达人NUP 98-HOXA 9（NHA 9）的转基因斑马鱼，这是一种在高危AML中发现的融合癌基因。胚胎发展为白血病前期状态，伴有贫血和骨髓细胞扩增，成鱼发展为骨髓增生性肿瘤（MPN）。我们利用该模型表明NHA 9增加造血干细胞的数量，并且NHA 9的致癌功能依赖于meis 1的下游激活、PTGS/考克斯通路和通过DNA甲基转移酶dnmt 1的基因组超甲基化。我们通过敲低meis 1或dnmt 1，以及用DNA（胞嘧啶-5）-甲基转移酶（DNMT）抑制剂或环氧合酶（考克斯）抑制剂进行药物治疗，恢复了NHA 9胚胎的正常造血。DNMT抑制剂将基因组甲基化降低至接近正常水平。引人注目的是，当我们将亚Monoclonal剂量的组蛋白脱乙酰酶抑制剂与DNMT抑制剂或考克斯抑制剂组合以阻断NHA 9对斑马鱼血液发育的影响时，我们发现了协同作用。我们的工作提出了NHA 9诱导的骨髓疾病的新药物靶点，并通过结合最小剂量的已知生物活性化合物提出了合理的治疗方法。
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.