Poster Presentation Epigenetics 2013

GADD45A expression in AML alters the DNA methylation and expression of key tumor suppressor genes (#131)

Richard D'Andrea 1 2 3 4 , Samya E Samaraweera 1 2 3 4 , Michelle Perugini 1 2 4 5 , Chung H Kok 1 6 7 , Ian D Lewis 1 3 4 5
  1. Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
  3. Division of Haematology, SA Pathology, Adelaide, SA, Australia
  4. Centre for Stem Cell Research, The University of Adelaide, Adelaide, SA, Australia
  5. Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia
  6. School of Medicine, The University of Adelaide, Adelaide, SA, Australia
  7. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

Acute Myeloid Leukaemia (AML) is a genetically diverse disease with poor survival rates. Despite the identification of key prognostic markers such as mutations of the FLT3 gene, treatment success remains poor. Hence the identification of new prognostic markers and therapeutic targets is vital for improving patient outcomes. Recent studies have identified mutations in several epigenetic modifier genes in AML and many of these mutations correlate with patient survival. Such mutations lead to changes in epigenetic regulation and in turn lead to altered expression of key tumor suppressor genes. The GADD45A gene is normally induced in response to genotoxic and cellular stress following which it coordinates the DNA repair and apoptotic response. We have shown that the proximal promoter of GADD45A is significantly methylated in a large percentage of AML patients. A high level of methylation in this regionwas also a predictor of poor overall survival in these patients (Perugini et al, 2013). Recent studies have also identified that GADD45A is involved in epigenetic regulation of specific downstream targets (Schafer et al, 2013). GADD45A mediates targeted active DNA demethylation through its interaction with DNA repair machinery. Therefore we propose that the DNA methylation of GADD45A in AML is likely to affect downstream epigenetic modulation of specific tumor suppressor genes, and this is likely to contribute to disease progression and response. In this study we identify potential targets of GADD45A-mediated DNA demethylation and we correlate gene expression data and global DNA methylation following over-expression of GADD45A in the AML cell line, MOLM-13. A number of the genes altered in response to GADD45A expression are involved in myeloid differentiation suggesting that a normal function of GADD45A maybe to promote differentiation, and the down-regulation of GADD45A may contribute to the differentiation block seen in AML. We have also identified a number of candidate targets of GADD45A with tumor suppressor function that have previously been reported to undergo epigenetic modulation in other cancers. We are now performing functional studies with these genes to investigate whether silencing of these genes contributes to the characteristics of AML through alteration of growth and survival.