Combined epigenetic therapy of acute myeloid leukemia: translational studies of in vivo induction of gene expression and DNA hypomethylation

DNA hypomethylating azanucleoside drugs provide active, non-intensive treatment of older AML/MDS patients, but the mechanisms governing their in vivo activity is as yet not fully understood. Using primary myeloid blasts from patients treated within the 4-arm randomized phase II "DECIDER" AML trial with 5-aza-2'-deoxycytidine (5-aza-dC, Decitabine, DAC) with or without the histone deacety-lase (HDAC) inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA, a differentiation-inducing agent active in acute promyelocytic leukemia), in Specific Aim 1 we will ask whether the epigenetic treatment induces distinct, early DNA methylation changes in the leukemic blasts only or also in normal, "bystander" T-cells and, in selected patients, in normal CD34+ hematopoietic precursors. Also we will address differential changes induced by Decitabine and 5-azacytidine in vivo, and whether de- and re-methylation is a random or non-random process in the primary cells studied. Specific Aim 2 focusses on the question: which treatment-induced DNA methylation changes correlate with mRNA expression changes? Here we also hope to generate a "response signature" to predict hematologic response by genes consistently derepressed/demethylated in the patients. In Specific Aim 3 we shall address which genes encoding Cancer/testis antigens are induced, and whether this is associated with demethylation of the genes. We hope that the generated methylome and transcriptome profiles of the cells from the epi-genetically treated leukemia patients will enable us to identify genome-wide targets of this treatment ap-proach, the extent of Decitabine DNA demethylating activity in malignant vs. normal blood cells, and hopefully a signature of clinical response to the epigenetic therapy. The long-term research goal is a bet-ter understanding of the mechanisms of action of epigenetically active agents in vivo, including those not directly linked to DNA hypomethylation.

DFG Programme Priority Programmes

Subproject of SPP 1463:  Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia

Participating Person Dr. Björn Hackanson