FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia
FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia
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DOI：
10.1016/j.ccr.2007.08.031
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发表时间：
2007-10-01
期刊：
影响因子：
50.3
通讯作者：
Gilliland, D. Gary
中科院分区：
文献类型：
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作者：
Lee, Benjamin H.;Tothova, Zuzana;Gilliland, D. Gary
尽管其具有已知的转化特性，但致白血病 FLT3-ITD 突变对造血干细胞和多能祖细胞以及造血分化的影响尚不清楚。我们报告了一种在小鼠 Flt3 基因座中携带 ITD 的小鼠模型，该模型会发展出类似于 CMML 的骨髓增殖性疾病，并进一步在人类 CMML 的子集中鉴定出 FLT3-ITD 突变。这些发现与动物中多能干细胞和祖细胞的数量、细胞周期和存活率的增加有关，这些增加以 ITD 剂量依赖性方式存在，这些动物的骨髓祖细胞区室内表现出改变，并且正常 B 细胞发育受阻。该模型提供了关于致癌酪氨酸激酶的组成性信号传导对造血祖细胞静止、功能和细胞命运的影响的见解。
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.