A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2.
A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2.
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DOI：
10.1084/jem.20110540
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发表时间：
2012-01-16
期刊：
影响因子：
--
通讯作者：
Pahl HL
中科院分区：
文献类型：
--
作者：
Kaufmann KB;Gründer A;Hadlich T;Wehrle J;Gothwal M;Bogeska R;Seeger TS;Kayser S;Pham KB;Jutzi JS;Ganzenmüller L;Steinemann D;Schlegelberger B;Wagner JM;Jung M;Will B;Steidl U;Aumann K;Werner M;Günther T;Schüle R;Rambaldi A;Pahl HL
在造血细胞中表达编码转录因子NF-E2的转基因的小鼠表现出骨髓增生性肿瘤的特征，包括血小板增多、Epo非依赖性集落形成、干细胞和祖细胞过量、白细胞增多和进展为急性髓性白血病。骨髓增生性肿瘤（MPN）的分子病理生理学仍然知之甚少。基于转录因子NF-E2通常在MPN患者中过表达的观察，独立于其他分子畸变的存在，我们产生了在造血细胞中表达NF-E2转基因的小鼠。这些小鼠表现出MPN的许多特征，包括血小板增多、白细胞增多、Epo非依赖性集落形成、特征性骨髓组织学、干细胞和祖细胞室的扩增以及自发转化为急性髓性白血病。MPN表型可移植到第二受体小鼠。NF-E2可以改变组蛋白修饰，并且NF-E2转基因小鼠显示组蛋白H3的低乙酰化。用组蛋白去乙酰化酶抑制剂（HDAC-I）伏立诺他治疗小鼠，恢复了组蛋白H3乙酰化的生理水平，降低了NF-E2表达，并使血小板数量正常化。类似地，用HDAC-I治疗的MPN患者表现出NF-E2表达的降低。这些数据确立了NF-E2在MPN病理生理学中的作用，并为研究表观遗传改变作为合理设计的MPN疗法的新靶点提供了分子基础。
Mice expressing a transgene encoding the transcription factor NF-E2 in hematopoietic cells exhibit features of myeloproliferative neoplasms, including thrombocytosis, Epo-independent colony formation, stem and progenitor cell overabundance, leukocytosis, and progression to acute myeloid leukemia. The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.
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影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
20.3
作者：
Akada, Hajime;Yan, Dongqing;Mohi, M. Golam
通讯作者：
Mohi, M. Golam
DOI：
10.1073/pnas.212389499
发表时间：
2002-10-29
影响因子：
11.1
作者：
Kiekhaefer, CM;Grass, JA;Bresnick, EH
通讯作者：
Bresnick, EH
影响因子：
15.3
作者：
Josefsson, Emma C.;James, Chloe;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
影响因子：
20.3
作者：
Kralovics, Robert;Teo, Soon-Siong;Skoda, Radek G.
通讯作者：
Skoda, Radek G.