The role of cellular senescence in prevention and treatment of pediatric leukemia
Frederick Mallette, PhD
In Canada, leukemia and lymphomas are the most common childhood cancer accounting altogether for 45 percent of new cases and 32 percent of deaths each year. Unfortunately, very little is known about the causes of pediatric leukemia but we know that genetic and epigenetic abnormalities contribute to the etiology of the disease. The main subtypes of pediatric leukemias are acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML), which involve a large variety of genetic alterations including point mutations, deletions and also chromosomal translocations. More than 200 genes have been found to be involved in translocations in childhood leukemia. The resulting chimeric protein usually displays an oncogenic constitutive kinase activity or novel transcriptional regulation. Fusion genes are the driving force of the leukemic process, but additional mutations are required for leukemogenesis.
To protect the organism against malignancies, cells have developed different responses toward oncogenic threat. Senescence is a critical tumor suppressive response that irreversibly stops the progression of cells exhibiting neoplastic potential. Multiple oncogenes such as Cdc6, cyclinE, Ras and STAT5 forces the cell to enter senescence. During senescence, cells do not respond to mitogenic signals and display changes of morphology due to the modification of the cytoskeleton. Senescent cells display dense chromatin structures termed senescence-associated heterochromatin foci (SAHF) that are involved in the stable repression of genes promoting the cell cycle. We intend to study the role of the chromatin structure during the senescence response to pediatric leukemic fusions by using genomic, proteomic, cytological and genetic approaches.