NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis
NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis
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DOI：
10.1111/j.1365-2141.2011.08810.x
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发表时间：
2011-10-01
影响因子：
6.5
通讯作者：
Berman, Jason N.
中科院分区：
文献类型：
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作者：
Forrester, A. Michael;Grabher, Clemens;Berman, Jason N.
NUP98-HOXA9 [t(7;11) (p15;p15)]与新生和治疗相关性急性髓性白血病（AML）的不良预后相关，并与慢性髓性白血病（CML）的原细胞危重有关。我们在斑马鱼基因1（pu）下设计了一种含有人类NUP98-HOXA9的可诱导转基因斑马鱼。1)启动子。NUP98-HOXA9干扰斑马鱼胚胎造血，以牺牲gata1a为代价上调spi1的表达。与分化程度较高的髓系细胞相关的标志物lcp1、lyz和mpx也有所升高，但升高程度低于spi1，这表明NUP98-HOXA9可能会损害早期髓系祖细胞的分化。辐照后，与对照组相比，表达nup98 - hoxa9的胚胎显示G2-M过渡的细胞数量增加，并且缺乏正常的凋亡反应，这可能是由于bcl2上调所致。这些数据表明，nup98 - hoxa9诱导的肿瘤发生可能是由造血缺陷和对DNA损伤的异常反应共同引起的。重要的是，23%的nup98 - hoxa9转基因成鱼在19-23月龄时发生骨髓增生性肿瘤（MPN）。总之，我们已经确定了转基因斑马鱼系的胚胎造血表型，随后发展为MPN。该工具为高通量体内化学修饰剂筛选提供了独特的机会，以识别高风险AML的新型治疗药物。
NUP98-HOXA9 [t(7;11) (p15;p15)] is associated with inferior prognosis in de novo and treatment-related acute myeloid leukaemia (AML) and contributes to blast crisis in chronic myeloid leukaemia (CML). We have engineered an inducible transgenic zebrafish harbouring human NUP98-HOXA9 under the zebrafish spi1(pu.1) promoter. NUP98-HOXA9 perturbed zebrafish embryonic haematopoiesis, with upregulated spi1expression at the expense of gata1a. Markers associated with more differentiated myeloid cells, lcp1, lyz, and mpx were also elevated, but to a lesser extent than spi1, suggesting differentiation of early myeloid progenitors may be impaired by NUP98-HOXA9. Following irradiation, NUP98-HOXA9-expressing embryos showed increased numbers of cells in G2-M transition compared to controls and absence of a normal apoptotic response, which may result from an upregulation of bcl2. These data suggest NUP98-HOXA9-induced oncogenesis may result from a combination of defects in haematopoiesis and an aberrant response to DNA damage. Importantly, 23% of adult NUP98-HOXA9-transgenic fish developed a myeloproliferative neoplasm (MPN) at 19-23 months of age. In summary, we have identified an embryonic haematopoietic phenotype in a transgenic zebrafish line that subsequently develops MPN. This tool provides a unique opportunity for high-throughput in vivo chemical modifier screens to identify novel therapeutic agents in high risk AML.