Grant: Project Grant

Despite advances in the treatment of acute leukemias over the past 20 years, they are still a leading cause of death by cancer before the age of 40. Also, their incidence grows exponentially after 60 years old and the overall survival 2 years after diagnosis is less than 15% in this group of patients. A better understanding of the mechanisms transforming a normal cell into a leukemic cell is essential to design new drugs and treatments and increase the survival of leukemic patients. Leukemia begins when a genetic event occurs in an hematopoietic stem cell in the bone marrow. It blocks its differentiation into terminally differentiated blood cells and gives a proliferation advantage over normal stem cells. Over time and with an increase number of leukemic cells, this uncontrolled proliferation leads to instability and additional mutations can occur. Such phenomenon is called "clonal evolution" and the additional mutations can induce a change in biology and/or drug resistance. Our team have developed a model that replicates the events leading to acute myeloid leukemia. We introduce a translocation frequently found in patients into human stem cells and then inject them into immunodeficient mice which develop human leukemias after 2-3 months. We can mimic the clonal evolution by mutating a gene in the RAS pathway into the transformed cells and evaluate its impacts on the biology of the leukemia in comparison to the unmutated cells. The RAS pathway has many genes that are recurrently mutated in human myeloid leukemia and will investigate the most frequent and important ones. Finally, we will use the generated leukemia to identify the changes in drug sensitivity to current and new drugs and uncover new therapeutic strategies to advance the treatment of acute myeloid leukemia.