Annesley Colleen E, Rabik Cara, Duffield Amy S, Rau Rachel E, Magoon Daniel, Li Li, Huff Vicki, Small Donald, Loeb David M, Brown Patrick
Department of Pediatrics, University of Washington, Seattle, WA, USA.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Oncotarget. 2018 Oct 19;9(82):35313-35326. doi: 10.18632/oncotarget.26238.
Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar mutations have been reported in adult patients with myelodysplastic syndrome (MDS). mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 () commonly co-occur with -mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a mutation (R394W), described in cases of human leukemia. We show that mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self-renewal of hematopoietic progenitor cells . We crossbred mice with knock-in mice, and show that mice with both mutations ( / ) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model.
威尔姆斯瘤1（WT1）是一种锌指转录调节因子，在多种恶性肿瘤中既被认为是肿瘤抑制因子，又被认为是致癌基因。在儿童和成人患者的10% - 15%正常核型急性髓系白血病（NK - AML）中，该基因的DNA结合结构域存在突变。在患有骨髓增生异常综合征（MDS）的成年患者中也报道了类似的突变。这些突变与NK - AML的治疗失败和不良预后独立相关。FMS样酪氨酸激酶3（FLT3）的内部串联重复（ITD）突变通常与FLT3 - 突变型AML共同出现，提示在白血病发生过程中起协同作用。FLT3突变在血液系统恶性肿瘤中的功能作用似乎很复杂，尚未完全阐明。在此，我们描述了一种在人类白血病病例中发现的FLT3突变（R394W）基因敲入小鼠模型的血液学表型。我们发现FLT3R394W小鼠会发展为骨髓增生异常综合征，在移植模型中其发生率为100%，表现为髓系祖细胞异常扩增，并证明造血祖细胞的自我更新增强。我们将FLT3R394W小鼠与基因敲入的p53小鼠杂交，结果显示同时具有两种突变（FLT3R394W/p53）的小鼠会发展出一种可移植的骨髓增生异常综合征/骨髓增殖性肿瘤（MDS/MPN），与任一单突变小鼠模型相比，具有更具侵袭性的特征。
