AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1
AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1
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DOI：
10.1038/leu.2008.53
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发表时间：
2008-06
期刊：
影响因子：
11.4
通讯作者：
Masataka Takeshita;M. Ichikawa;Eriko Nitta;S. Goyama;Takashi Asai;Seishi Ogawa;S. Chiba;Mineo Ku
中科院分区：
文献类型：
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作者：
Masataka Takeshita;M. Ichikawa;Eriko Nitta;S. Goyama;Takashi Asai;Seishi Ogawa;S. Chiba;Mineo Ku
t（3; 21）在慢性髓性白血病和继发性白血病的母细胞危象中观察到的染色体易位导致嵌合蛋白AML 1-Evi-1的形成，其抑制野生型AML 1功能。AML 1功能的丧失导致造血祖细胞的扩增，而这不足以发展成白血病。为了确定AML 1-Evi-1发挥完全致白血病潜力的基本机制，我们将AML 1-Evi-1及其突变体引入小鼠骨髓细胞中，并通过集落再铺板测定来评估它们的转化活性。当Evi-1的任何已知功能结构域从嵌合蛋白中缺失时，AML 1-Evi-1的转化活性丧失，并且Evi-1的强制表达不转化AML 1缺失的骨髓细胞。与MLL-ENL和AML 1-ETO白血病相关嵌合蛋白不同，AML 1-Evi-1只能转化造血干细胞组分。此外，AML 1-Evi-1转化的细胞显示出与AML 1-ETO转化的细胞不同的细胞标志物谱，其也抑制AML 1功能。因此，AML 1-Evi-1的致白血病活性可能是由于造血干细胞组分中与MLL-ENL或AML 1-ETO激活的分子机制不同的分子机制的激活。
The t (3; 21) chromosomal translocation seen in blastic crisis of chronic myeloid leukemia and secondary leukemias results in a formation of a chimeric protein AML1-Evi-1, which suppresses wild-type AML1 function. Loss of AML1 function causes expansion of hematopoietic progenitor cells, whereas it is not sufficient for the development of leukemia. To identify essential mechanisms through which AML1-Evi-1 exerts full leukemogenic potential, we introduced AML1-Evi-1 and its mutants in murine bone marrow cells, and evaluated their transforming activities by colony replating assays. The transforming activity of AML1-Evi-1 was lost when any of the known functional domains of Evi-1 was deleted from the chimeric protein, and forced expression of Evi-1 did not transform the AML1-deleted bone marrow cells. Unlike the MLL-ENL and AML1-ETO leukemia-related chimeric proteins, AML1-Evi-1 could transform only the hematopoietic stem cell fraction. Moreover, AML1-Evi-1-transformed cells show a cell-marker profile distinct from that of the cells transformed by AML1-ETO, which also suppresses AML1 function. Thus, leukemogenic activity of AML1-Evi-1 may be due to activation of molecular mechanisms distinct from those activated by MLL-ENL or AML1-ETO in the hematopoietic stem cell fractions.