Leukemias represent nearly a third of all cancers diagnosed in children in Canada, and while progress has been made for the treatment of the majority of these leukemias, acute myeloid leukemia (AML) stands out as an exception, with a strikingly poor outcome where only slightly more than half of all patients will be cured. Research into the genetic causes of AML has identified some recurrent mutations, such as rearrangements of the MLL gene which are present in ~65% of infant AML samples, but the development of the disease is still not fully understood. Our lab has used a high throughput technology for RNA and DNA sequencing to study both MLL-rearranged pediatric AML samples and a novel human cord blood model system we have developed to create human MLL-rearranged leukemias.
The comparison of these data to normal samples has clearly revealed 39 genes specifically expressed in MLL-rearranged leukemias. We will investigate one specific candidate gene, RET, in more detail because it is known to be involved in other types of cancer and also because we have shown that it is essential in MLL-AF9 AML. We will also look at leukemia specific changes in alternative splicing, which allows individual genes to make different versions of a protein, and epigenetic changes, which control how DNA is physically arranged and used in the cell. Lastly, we will look at how normal genetic variation in the human population impacts gene function and helps to promote cancer.
This work will provide new understanding into the requirements for leukemia development when the MLL gene is rearranged and it will also clarify which requirements are specific to certain types of leukemia. In addition, the systematic analysis of the initial candidate genes we have found will reveal both novel biomarkers for AML and potential therapeutic targets for this disease.