Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBPα Mutant AML
Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBPα Mutant AML
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DOI：
10.1016/j.ccr.2009.09.036
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发表时间：
2009-11-03
期刊：
影响因子：
50.3
通讯作者：
Nerlov, Claus
中科院分区：
文献类型：
--
作者：
Bereshchenko, Oxana;Mancini, Elena;Nerlov, Claus
在这里，我们使用小鼠的敲门突变来模拟人类急性髓系白血病获得性CEBPA突变的谱。我们发现C-末端C/EBPα突变以细胞内的方式增加长期造血干细胞(LT-HSCs)的增殖，并破坏正常的HSC稳态，导致癌前HSCs的扩张。然而，这种突变损害了造血干细胞的髓系编程，并在纯合时阻碍了髓系的承诺。相反，N端C/EBPα突变对于HSC的扩张是沉默的，但允许形成承诺的髓系祖细胞，即白血病启动细胞的模板。N端和C端C/EBPα突变的组合结合了这两个特征，加速了疾病的发展，并解释了这种CEBPA突变的临床流行情况。
We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.