Fischer Meike, Schwieger Maike, Horn Stefan, Niebuhr Birte, Ford Anthony, Roscher Susanne, Bergholz Ulla, Greaves Mel, Löhler Jürgen, Stocking Carol
Molecular Pathology Group, Heinrich-Pette-Institut für Experimentelle Immunologie und Virologie, D-20251 Hamburg, Germany.
Oncogene. 2005 Nov 17;24(51):7579-91. doi: 10.1038/sj.onc.1208931.
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. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired 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. Despite 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 findings 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. Furthermore, 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.
产生TEL/AML1融合蛋白的t(12;21)易位是儿童癌症中最常见的基因损伤。利用骨髓移植模型，我们证明TEL/AML1的表达影响正常造血分化，导致具有Sca1(+)/Kit(hi)/CD11b(+)表型的早期祖细胞区室在体内积累并持续存在，且自我更新能力增强，体外再接种试验证明了这一点。这些细胞的分化并未受阻，但由TEL/AML1转导的祖细胞产生成熟血细胞的频率较低。在前B细胞区室中明显观察到分化受损，导致体内早期祖细胞成比例增加，这与t(12;21)急性淋巴细胞白血病（ALL）的表型一致。尽管体内多能祖细胞和B细胞祖细胞都有积累，但在超过1年的观察期内未观察到白血病诱导现象。这些结果与同卵双胞胎患ALL的研究结果一致，表明TEL/AML1在子宫内产生一个白血病前期克隆，该克隆以临床隐匿的方式持续数年。此外，我们的研究表明，TEL/AML1的尖结构域招募转录抑制因子并指导与TEL/AML1或野生型TEL的寡聚化，对于观察到的分化损伤至关重要，且不能被另一个寡聚化结构域替代。
