Analysis of the interaction of the T-cell oncoproteins Scl and Lmo2 in T cell acute lymphoblastic leukaemia

白血病细胞经常包含染色体的改变，这些改变通过引起促癌基因的表达来促进白血病的产生。在T细胞急性淋巴细胞白血病（T- all）的情况下，染色体改变最常见的目标是干细胞白血病基因，或SCL。在白血病细胞中，SCL蛋白被发现与另一种叫做Lmo2的蛋白相关，Lmo2基因也因T-ALL的染色体改变而被激活。人们认为这两种蛋白质必须相互结合才能引起白血病，但这从未得到证实。该项目旨在测试清除SCL和Lmo2是否能够阻止它们引发的白血病的进展。我们将通过过表达SCL和Lmo2在小鼠体内建立白血病，然后去除这些基因来观察白血病是否被治愈。然后，我们将测试去除内源性SCL蛋白是否能够阻止Lmo2引发的白血病的发生和进展。我们将通过去除过表达Lmo2的小鼠的SCL来做到这一点。最后，我们将产生不能与Lmo2相互作用的突变型SCL蛋白，并在小鼠中与Lmo2共同表达，以评估它们是否能够与Lmo2合作导致白血病。我们预测这些不能与Lmo2结合的突变体将不能与Lmo2合作导致白血病。这将确定这些蛋白质的区域，这些区域可以用作抗白血病药物开发的靶标。

Leukaemic cells frequently contain alterations to the chromosomes which contribute to the generation of the leukaemia by causing the expression of cancer-promoting genes. In the case of T cell acute lymphoblastic leukaemia (T-ALL), the most frequent target of chromosomal alterations is the Stem Cell Leukaemia gene, or SCL. In leukaemic cells, the SCL protein is found to be associated with another protein, called Lmo2, the gene for which is also activated due to chromosomal alterations in T-ALL. It is thought that these two proteins must bind each other to cause leukaemia, but this has never been proven. This project aims to test whether removal of SCL and Lmo2 is able to stop the progress of leukaemias which they initiate. We will do this by overexpressing SCL and Lmo2 to establish leukaemia in mice, then removing these genes to see if the leukaemia is cured. We will then test whether removal of the endogenous SCL protein is able to stop the onset and progress of leukaemias initiated by Lmo2. We will do this by removing SCL in mice which overexpress Lmo2. Lastly we will generate mutant SCL proteins which are unable to interact with Lmo2, and co-express these along with Lmo2 in mice to assess whether they are able to co-operate with Lmo2 in causing leukaemia. We predict these mutants which are unable to bind to Lmo2 will be unable to co-operate with it in causing leukaemia. This will identify regions of these proteins which can be used as targets for anti-leukaemia drug development.