Grant: Operating Grant

Acute lymphoblastic leukemia is the most common childhood cancer and 25% of those are of T cell origin (T-ALL). The latter is considered a high risk group in ALL and approximately 20% of childhood and 60% of adult ALL patients succumb to this disease. We have previously shown that the aberrant activation of three oncogenes, namely SCL, LMO1/2 and Notch1 together with a normal signal from a cell surface receptor might be sufficient to induce T-ALL in mouse models. T lymphocytes are produced in the thymus and these thymocytes normally proliferate and differentiate in response to the pre-TCR and to their environment in the thymus. Surprisingly, these normal responses accelerate leukemia onset. In the present research proposal, we will define how oncogenes confer the capacity for extended division to thymocytes that have a finite life span and how tumor suppressors restraint this oncogenic activity. In the long term, our observations may improve the capacity to direct clinical intervention towards thymocytes that are transformed by the oncogenes. The high cure rate in childhood T-ALL is a success story in oncology. However, treatments have sequelae and cure is not always assured. For example, dexamethasone is a drug which is successfully used in T-ALL. However, dexamethasone may later cause osteonecrosis, due to loss of some sites in the bones. Therefore, understanding the root of the disease in specific subpopulations in the thymus may allow investigators to specifically focus their efforts to develop therapies that are directed towards abnormal processes in these thymocytes, thereby minimizing general drug toxicities.