Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model
Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model
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DOI：
10.1182/blood-2011-10-382283
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发表时间：
2012-03-22
期刊：
影响因子：
20.3
通讯作者：
Small, Donald
中科院分区：
文献类型：
--
作者：
Greenblatt, Sarah;Li, Li;Small, Donald
FLT 3通过内部串联重复（ITD）的组成性激活是急性髓性白血病（AML）中最常见的分子改变之一。在骨髓增生异常综合征患者中，在进展为AML之前和期间也观察到FLT 3/ITD突变。以前的工作表明，FLT 3/ITD突变插入到小鼠Flt 3基因诱导骨髓增生性肿瘤，但不进展为急性白血病，这表明需要额外的合作事件。因此，我们将FLT 3/ITD突变与涉及Nup 98-HoxD 13（NHD 13）融合基因转基因表达的骨髓增生异常综合征模型相结合。表达FLT 3/ITD和NHD 13转基因的小鼠发生AML，具有100%的潜伏期和短潜伏期。这些白血病由突变型FLT 3表达驱动，并且对FLT 3酪氨酸激酶抑制剂治疗敏感。我们还观察到这些AML中野生型Flt 3等位基因的自发丢失，进一步模拟了在具有FLT 3激活突变的人AML中观察到的杂合性丢失现象。由于对FLT 3抑制剂的耐药性仍然是一个重要的临床问题，因此该模型可能有助于识别协同信号通路中的新分子靶点。（血。2012;119（12）：2883-2894）
Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways. (Blood. 2012;119(12):2883-2894)