Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model
Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model
复制标题
DOI：
10.1038/sj.onc.1208931
复制
发表时间：
2005-11-17
期刊：
影响因子：
8
通讯作者：
Stocking, C
中科院分区：
文献类型：
--
作者：
Fischer, M;Schwieger, M;Stocking, C
产生TEL/AML 1融合蛋白的t（12;21）易位是儿童癌症中最常见的遗传病变。使用骨髓移植模型，我们证明了TEL/AML 1表达影响正常造血分化，导致具有Sca 1（+）/Kit（hi）/CD 11b（+）表型的早期祖细胞隔室的体内积累和持久性以及增加的自我更新能力，如通过体外再铺板测定所证明的。这些细胞的分化没有被阻断，但是由TEL/AML 1转导的祖细胞产生的成熟血细胞的频率很低。在前B细胞区室中显著观察到分化受损，导致体内早期祖细胞成比例增加，与t（12;21）ALL表型一致。尽管多能祖细胞和B-祖细胞在体内蓄积，但在超过1年的观察期内未观察到白血病诱导。这些结果是一致的。结果显示，TEL/AML 1在子宫内产生白血病前克隆，并以临床隐蔽的方式持续数年。此外，我们的研究表明，TEL/AML 1的点域，招募转录抑制因子，并指导与TEL/AML 1或野生型TEL的寡聚化，是所观察到的分化障碍所必需的，不能被另一个寡聚化结构域取代。
The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1(+)/Kit(hi)/CD11b(+) phenotype and an increased self- renewal capacity, as documented by replating assays in vitro. Differ entiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1- transduced progenitors is low. Impa ired differentiation is prominently observed in the pro- B- cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Desp ite the accumulation of both multipotent and B- cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with. ndings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Fur thermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.