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.
|Publisher||Erasmus University (Institute)|
|Promotor||Pieters, R. (Rob)|
|Sponsor||The studies described in this thesis were financially supported by grants from the Sophia Foundation for Medical Research (SSWO grants 495 and 600). We gratefully acknowledge Amgen, Celgene, the Erasmus University Rotterdam (EUR), Eusapharma, Janssen-Cilag, the Jurriaanse Foundation, MosaMedix, MRC Holland, NeXins Research, Novartis, the Pediatric Oncology Foundation Rotterdam (KOCR), and Sanofi for providing financial support for the printing of this thesis.|
|Keywords||DNA methylation, MLL, epigenetics, infant acute lymphoblastic leukemia|
Stumpel, D.J.P.M.. (2012, September 5). Epigenetics in MLL-rearranged infant Acute Lymphoblastic Leukemia. Erasmus University (Institute). Retrieved from http://hdl.handle.net/1765/37163