Morrow Michelle, Horton Sarah, Kioussis Dimitris, Brady Hugh J M, Williams Owen
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London, United Kingdom.
Blood. 2004 May 15;103(10):3890-6. doi: 10.1182/blood-2003-10-3695. Epub 2004 Jan 15.
The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality yet identified in any pediatric leukemia and gives rise to the TEL-AML1 fusion product. To investigate the effects of TEL-AML1 on hematopoiesis, fetal liver hematopoietic progenitor cells (HPCs) were transduced with retroviral vectors expressing this fusion protein. We show that TEL-AML1 dramatically alters differentiation of HPCs in vitro, preferentially promoting B-lymphocyte development, enhancing self-renewal of B-cell precursors, and leading to the establishment of long-term growth factor-dependent pre-B-cell lines. However, it had no effect on myeloid development in vitro. Further experiments were performed to determine whether TEL-AML1 also demonstrates lineage-specific activity in vivo. TEL-AML1-expressing HPCs displayed a competitive advantage in reconstituting both B-cell and myeloid lineages in vivo but had no effect on reconstitution of the T-cell lineage. Despite promoting these alterations in hematopoiesis, TEL-AML1 did not induce leukemia in transplanted mice. Our study provides a unique insight into the role of TEL-AML1 in leukemia predisposition and a potential model to study the mechanism of leukemogenesis associated with this fusion.
t(12;21)(p13;q22)易位是目前在任何小儿白血病中发现的最常见的染色体异常，它会产生TEL-AML1融合产物。为了研究TEL-AML1对造血作用的影响，用表达这种融合蛋白的逆转录病毒载体转导胎肝造血祖细胞（HPC）。我们发现，TEL-AML1在体外显著改变HPC的分化，优先促进B淋巴细胞发育，增强B细胞前体的自我更新，并导致建立长期依赖生长因子的前B细胞系。然而，它在体外对髓系发育没有影响。进行了进一步实验以确定TEL-AML1在体内是否也表现出谱系特异性活性。表达TEL-AML1的HPC在体内重建B细胞和髓系谱系方面显示出竞争优势，但对T细胞谱系的重建没有影响。尽管TEL-AML1促进了造血过程中的这些改变，但它并未在移植小鼠中诱发白血病。我们的研究为TEL-AML1在白血病易感性中的作用提供了独特见解，并为研究与这种融合相关的白血病发生机制提供了一个潜在模型。
