Chromosomal translocation genes and their protein interactions in cancer

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.

The programme will be a continuation of my current MRC programme grant and builds on some new observations about chromosomal translocations in cancer development. We will focus on three related areas involving chromosomal translocation genes, viz. the LMO2 translocation gene protein in cancer and in haematopoiesis and synergy with the IL2 receptor gamma common chain in leukaemia; cancer lineage control by chromosomal translocation fusion genes such as MLL-AF4, ENL and AF9 and BCR-ABL; cancer lineage control by mutant signaling molecules resulting in liver neoplasias and a new model of haemangioblastoma. We will refine further our de novo translocation (translocator) technology to incorporate reporter genes for tracking cancer initiating cells and to incorporate co-operating oncogenes to study the role of fusions genes. We will develop new approaches to study and interfere with protein-protein interactions in cancer. The new technologies proposed that will add further levels of complexity to more accurately recapitulate human disease counterparts and the new approaches will be transferable to other labs, for instance resources such as the proposed serially targeted ES cells.

The research objectives are therefore to understand the function chromosomal translocation genes and their protein interactions in cancer and to solve basic problems in haematopoiesis and cancer biology. For exploitation of the research results, we will contribute knowledge for the unmet need of cancer target validation and corroborating protein complexes as targets for therapy. The programme is technology driven including new ways to produce highly specific and rapid models of the effects of chromosomal translocation genes, methods to identify natural components of protein complexes and approaches to confirm that chromosomal translocation genes or mutant proteins are valid drug targets. The latter is an important spin-off as a precursor to expensive and lenghty drug development.

The work proposed will have a major impact on understanding how chromosomal translocations control the transition from the cancer initiating cell through to overt, symptomatic cancer and the control of lineage specification when the translocation occurs in a pluripotent or multipotent cell. Further, the work will impact on understanding the molecular events that underlie lineage reassignment when a translocation takes place in a semi-committed cell that retains some plasticity for differentiation. Thus the benefits of the work will mainly and initially be in the academic arena, but including and beyond cancer biology, because we will have described further functions of transcription and signaling in the process of cell fate decision. Further, the validation of chromosomal translocation proteins as cancer targets will eventually be used by the biotechnology and pharmaceutical industry to guide development of diagnostic, prognostic and therapeutic strategies. Time frames for these benefits will vary, with the therapeutic outcome being the longest to achieve. Typically greater than 20 years is needed from academic research findings to be translated to the benefit of public health. It is, however, hoped that directed translational research will accelerate this process and the gathering knowledge of mutant proteins in cancer will facilitate greater focus on the development of public health applications.