AML1 mutations induced MDS and MDS/AML in a mouse BMT model
AML1 mutations induced MDS and MDS/AML in a mouse BMT model
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DOI：
10.1182/blood-2007-01-068346
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Kitamura, Toshio
中科院分区：
文献类型：
--
作者：
Watanabe-Okochi, Naoko;Kitaura, Jiro;Kitamura, Toshio
骨髓增生异常综合征（MDS）是一种造血干细胞疾病，其特征在于三系发育异常和对急性髓细胞性白血病（AML）的易感性。MDS的异质性阻碍了对MDS分子基础的分析。最近，转录因子AML 1/RUNX 1的突变已经在15%至40%的MDS难治性贫血伴原始细胞过多（RAEB）和MDS/AML中被确定。我们进行了小鼠骨髓移植（BMT）使用骨髓细胞与AML 1突变体转导。大多数小鼠在骨髓移植后4至13个月内出现MDS和MDS/AML样症状。有趣的是，在确定的整合位点中，邪恶似乎与在Runt同源结构域（D171 N）中具有点突变的AML 1突变体协作，以诱导具有相同表型的MDS/AML，其特征在于显著的肝脾肿大、骨髓发育不良、白细胞增多和双表型表面标志物。AML 1-D171 N和Evil之间的协作通过BMT模型得到证实，其中AML 1-D171 N和Evil的共表达诱导了具有相同表型的急性白血病，具有短得多的潜伏期。另一方面，C端截短的AML 1突变体（S291 fsX 300）在移植小鼠中诱导全血细胞减少伴红系发育不良，随后进展为MDS-RAEB或MDS/AML。因此，我们已经开发了一个有用的小鼠模型MDS/AML，应该有助于理解MDS的分子基础和MDS的进展，以明显的白血病。
Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trillneage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS-refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified,Evil seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evil was confirmed by a BMT model where coexpression of AML1-D171N and Evil induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.