Modeling of C/EBPα mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells
Modeling of C/EBPα mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells
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DOI：
10.1016/j.ccr.2008.02.008
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发表时间：
2008-04-01
期刊：
影响因子：
50.3
通讯作者：
Nerlov, Claus
中科院分区：
文献类型：
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作者：
Kirstetter, Peggy;Schuster, Mikkel B.;Nerlov, Claus
CEBPA基因突变存在于7%-10%的急性髓细胞白血病（AML）患者中。然而，没有遗传模型存在，证明其病因相关性。为了模拟影响CEBPA的最常见的突变，即那些导致42 kDa C/EBP α亚型（p42）丢失而保留30 kDa亚型（p30）的突变，我们修饰了小鼠Cebpa基因座，使其仅表达p30。p30支持粒细胞-巨噬细胞祖细胞的形成。然而，p42是控制髓系祖细胞增殖所必需的，p42缺陷的小鼠发展为AML，并具有完全转移。p42缺陷型白血病可以通过Mac 1（+）c-Kit（+）群体转移，该群体仅在受体小鼠中产生髓系细胞。该群体针对正常Mac 1（+）c-Kit（+）祖细胞的表达谱显示了与MLL-AF 9转化的AML共有的特征。
Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBP alpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1(+)c-Kit(+) population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1(+)c-Kit(+) progenitors revealed a signature shared with MLL-AF9-transformed AML.