Lobato M Natividad, Metzler Markus, Drynan Lesley, Forster Alan, Pannell Richard, Rabbitts Terence H
MRC Laboratory of Molecular Biology, Cambridge, UK.
J Natl Cancer Inst Monogr. 2008(39):58-63. doi: 10.1093/jncimonographs/lgn022.
Recurrent reciprocal chromosomal translocations are present in more than 50% of leukemias. A deeper understanding of how they affect cancer initiation is essential for evaluating the origins of cancer and the potential for therapy based on the translocation products. Mouse models of chromosomal translocations are required for this. Here we summarize three methodologies developed in our laboratory to model chromosomal translocations (knock-in, translocator, and invertor methods). We have used these models to study leukemias caused by fusions of the mixed lineage leukemia (MLL) gene and the Ews-ERG fusion gene to evaluate oncogenicity and elucidate some general principles about translocation products. We show that MLL fusions have the capacity to cause hematopoietic tumors only if expressed in permissive cells and that the Mll-Enl fusion can cause lineage reassignment if the chromosomal translocation occurs in lineage noncommitted progenitors. The leukemia-initiating cells generated by Mll fusions or by Ews-ERG fusion can be committed cells within the hematopoietic pathway. Our translocation mimic models are applicable to any human reciprocal chromosomal translocation.
超过50%的白血病存在复发性相互染色体易位。深入了解它们如何影响癌症起始对于评估癌症起源以及基于易位产物的治疗潜力至关重要。为此需要染色体易位的小鼠模型。在此，我们总结了我们实验室开发的三种模拟染色体易位的方法（敲入法、易位体法和倒位体法）。我们已使用这些模型研究由混合谱系白血病（MLL）基因融合和Ews-ERG融合基因引起的白血病，以评估致癌性并阐明一些关于易位产物的一般原则。我们表明，MLL融合只有在允许的细胞中表达时才有能力引发造血肿瘤，并且如果染色体易位发生在谱系未定向祖细胞中，Mll-Enl融合可导致谱系重新分配。由Mll融合或Ews-ERG融合产生的白血病起始细胞可以是造血途径内的定向细胞。我们的易位模拟模型适用于任何人类相互染色体易位。
