A single broken chromosome can fuse two proteins together, creating a hybrid molecule that drives cancer—and researchers plan to track exactly where and how this happens. This matters because most human cancers contain these abnormal chromosomes, yet the resulting fusion proteins are notoriously difficult to study and even harder to block with drugs. The team will focus on three proteins—MLL, LMO2, and KRAS—that are already known to play roles in leukaemia and other cancers. KRAS alone is altered in about 25% of all human cancers. The researchers have developed a new fast method to attach tracking devices to cancer cells, allowing them to watch where a cancer starts and where it ends up, even when the original site (such as bone marrow) differs from where tumours later appear (such as the brain). If successful, this work could map the origins of different cancers, explain why cancer cells move from one place to another, and identify new drug targets. The programme is fundamentally curiosity-driven—it aims to solve basic puzzles in blood development, bone marrow biology, and cancer formation. Similar fundamental studies of chromosomal translocations in the past have led directly to targeted therapies for leukaemia.
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Specific chromosomal translocations are abnormal chromosomes found in most human cancers and are part of the reason why people get cancer. Each cancer has a special type of abnormal chromosome and this change in the structure of the chromosome causes proteins to work incorrectly or even to joining with other proteins to give what is known as fusion or chimaeric proteins. These are invariably proteins inside the cancer cell that function by finding partners and binding to them, often with other partner proteins then joining to make bigger and bigger complexes. We plan to work out how the proteins from chromosomal translocation contribute to cancer by studying what happens when cancers start and which proteins they like to bind to in normal cells and in cancer cells. Many cancers occur in patients because of these abnormal proteins but these are hard to understand and to find drugs that will block them. Some proteins in leukaemias (such as MLL and LMO2) have been extensively studied in both cancer and normal cells and one challenge is to understand how the abnormal expression influences the type of cancer and to determine at which level the protein influences the process of cancer formation. Thus, if a translocation occurs in the cancer forming cell (called a cancer initiating cell), there will be changes in the way the cells works with its RNA and protein milieu being altered. We will try to find out how the two proteins work and investigate the role of a protein called KRAS, that is different from normal in about 25% of all human cancers. RAS can be expressed in one location (e.g. bone marrow) but cancers can arise elsewhere (e.g. brain). We will implement a new fast method to add tracking devices to cancer cells in order that we can see where they start and where they finish in cancer. We will be able to use this new technology to question MLL and LMO2 and RAS proteins. The studies will contribute to mapping cancer origins, to understanding of the puzzling assortment of facets of cancer, why cancer cells move from one place to another in cancer and lead to development of new therapies. The programme will also contribute to understanding of basic problems in blood development, bone marrow development and cancer biology and to the unmet need of finding and confirming cancer drug targets.
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