Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage.
Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage.
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DOI：
10.1084/jem.20050067
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发表时间：
2005-07-04
期刊：
影响因子：
--
通讯作者：
Nerlov C
中科院分区：
文献类型：
--
作者：
Porse BT;Bryder D;Theilgaard-Mönch K;Hasemann MS;Anderson K;Damgaard I;Jacobsen SE;Nerlov C
CCAAT/增强子结合蛋白(C/EBP)α是一种骨髓特异性转录因子，将谱系承诺与终端分化和细胞周期阻滞结合在一起，在9%的急性髓性白血病（AML）患者中发现突变。我们之前的研究表明，将C/EBPα通过抑制E2F来阻断细胞周期进程的能力与其作为转录激活因子的功能分离的突变会损害中性粒细胞和脂肪谱系的体内发育。我们现在表明，这种突变增加了骨髓（BM）髓系祖细胞增殖的能力，并使小鼠易患粒细胞性骨髓增殖性疾病和骨髓间室的转化。这两种表型都可移植到受致死性辐射的受体中。骨髓转化的特征是粒细胞分化受阻，成髓细胞和早幼髓细胞聚集，骨髓祖细胞群扩增，这些都是AML的特征。观察到循环成髓细胞和肝脏白细胞浸润，但没有血小板减少、贫血和白细胞计数升高（通常与aml相关）。这些结果表明，破坏C/EBPα的细胞周期调节功能足以启动粒细胞谱系的AML样转化，但仅部分影响AML的周围病理。
CCAAT/enhancer binding protein (C/EBP)α is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBPα to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations—all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count—normally associated with AML—were absent. These results show that disrupting the cell cycle regulatory function of C/EBPα is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.
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DOI：
10.1073/pnas.94.10.5302
发表时间：
1997-05-13
影响因子：
11.1
作者：
He, LZ;Tribioli, C;Pandolfi, PP
通讯作者：
Pandolfi, PP
DOI：
10.1084/jem.194.7.941
发表时间：
2001-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bryder D;Ramsfjell V;Dybedal I;Theilgaard-Mönch K;Högerkorp CM;Adolfsson J;Borge OJ;Jacobsen SE
通讯作者：
Jacobsen SE
影响因子：
20.3
作者：
D'Alo, F;Johansen, LM;Tenen, DG
通讯作者：
Tenen, DG
影响因子：
11.4
作者：
Kaeferstein, A;Krug, U;Verbeek, W
通讯作者：
Verbeek, W
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH