Abstract
Aim: There is currently little information on epigenetic therapy in in vivo preclinicalmodels of acute myeloid leukemia (AML). The study was designed to establish apreclinical model for the validation and optimization of epigenetic therapies and othertreatment strategies. Materials and Methods: In this study we first characterized the response of normalimmunodeficient mice to different doses of 5-aza-2’-deoxycytidine (AZA), valproicacid (VPA) and all-trans retinoic acid (ATRA). This allowed us to define anoptimized 28-day protocol (AZA+VPA 7 days followed by 21 days ATRA) showinglow toxicity and associated with efficient global DNA demethylation and histoneacetylation of bone marrow mononuclear cells. Results: AML xenografts of 5 non-promyelocytic AML patients were treated with thedefined protocol. One out of 5 demonstrated reduced disease burden, celldifferentiation (increase of CD15, CD11b and to some extent CD14 positive cells anddecrease of CD34+ population) and reduced capacity in reinitiating leukemia insecondary recipients.Conclusion: These findings mimic results of clinical trials and indicate that AMLxenografts may provide useful preclinical models to optimize epigenetic therapies.
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