Epigenetics in MLL-rearranged infant Acute Lymphoblastic Leukemia

Nowadays the cure rate for children diagnosed with acute lymphoblastic leukemia (ALL) has exceeded 80%. Although this is considered to be one of the major successes in pediatric oncology, the subgroup of patients that did not benefit from the improved therapeutic strategies should not be overlooked. When ALL is diagnosed in an infant (< 1 year of age) the overall survival rate is less than 50%. Whereas with the currently available treatment protocols usually complete remission is achieved, relapses that are resistant for the most common chemotherapeutics typically occur within one year from diagnosis. The majority of infants with ALL (~80%) carry balanced chromosomal translocations involving the MLL gene. These translocations are independent predictors of a dismal clinical outcome. Treating infant ALL with MLL translocations is one of the current challenges in pediatric oncology. The studies described in this thesis demonstrate that ALL in infants is characterized by abnormal epigenetic regulation, i.e. aberrant DNA methylation at a large number of gene promoters. This aberrant DNA methylation leads to erroneous gene activation and inactivation which may have facilitated leukemia development. This thesis also revealed that certain epigenetic drugs can partially reverse the abnormal DNA methylation. In addition, these drugs efficiently kill the leukemic cells from infants with ALL in vitro. Some of these drugs even down-regulate the MLL translocation which was thought to be the driving force behind this type of leukemia. With these pre-clinical studies the first steps have been taken towards improved therapies for infant ALL with MLL translocations

Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. Methods For this, we performed gene expression profiling after siRNA-mediated repression of MLLAF4, MLL-ENL, and AF4-MLL in MLL -rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. Results Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were aff