This project is focussed upon genes that govern that proliferation and differentiation of hematopoietic cells and the alterations that promote leukemia and lymphoma. Advantages of the murine hematopoietic system include numerous lineage markers, cloned growth factors, clonogenic assays, an effective in vivo repopulation system and candidate lineage commitment genes upon the hematopoietic compartment, retroviral vectors permitting long term in vivo expression have been developed over the last three years. The power of this approach is illustrated by our proliferation and that the hybrid bcr-abl gene generated similarly in chronic myeloid leukemia [CML] promotes autonomy in myeloid cell lines and elicits myeloproliferative syndromes in vivo. Purchase on genes that might help to govern hematopoiesis was provided by our finding that a number of homebox genes are expressed within this compartment, and that one homebox gene was activated by proviral insertion in a myeloid leukemia. Research over the next three years will exploit retroviral vectors to test the biological effects of oncogenes and other putative regulatory genes upon primitive hematopoietic cells, in order to create murine models for acute and chronic leukemias. The recently observed profound myeloproliferative effects of the bcr-abl gene suggest that an animal model for CML should soon be obtainable. As hematopoietic stem cells can now be purified, another major goal will beta establish permanent stem cell lines that retain multipotent character. Since relatively little is known about the genes that restrain uncontrolled proliferation [anti-oncogenes], the role in leukemogenesis of the known anti-oncogenes Rb and p53 will be investigated, and a strategy for isolating new anti-oncogenes based upon retroviral insertional mutagenesis will be explored. To identify potential lineage commitment genes, a search is underway for genes expressed in specific hemopoietic lineages and bearing the DNA-binding signature of the homebox, the Zn finger and the helix-loop-helix domain. This work has recently uncovered novel homebox genes with lineage-specific expression and unexpectedly revealed that a homebox gene can be oncogenic. Significance: These studies should help to identify initiating events in leukemias and lymphomas, generate new animal models for leukemogenesis, clarify the biological effects of oncogenes and anti-oncogenes and reveal novel genes that help to govern lineage commitment. Thus, the research should help to elucidate the normal genetic control of hematopoiesis as well as the pathways to tumorigenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Walter and Eliza Hall Institute Medical Research
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VIC, -3052
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