Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Combined epigenetic therapy of AML: in vitro and translational studies of induction of gene expression and DNA hypomethylation

DNA hypomethylating agents provide active, non-intensive treatment of older AML/MDS patients, but the mechanisms governing their in vivo activity as as yet not fully understood.
Using myeloid cell lines, and primary myeloid blasts from patients treated within a 4-arm randomized phase II AML trial studing 5-aza-2'-deoxycytidine (5-aza-dC, decitabine, DAC) with or without the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA, a differentiation-inducing agent active in acute promyelocytic leukemia) in a 2x2 factorial design, we will ask:

a) is expression of the genes encoding the RA receptor (RAR)-ß2 and the highly immunogenic Cancer/testis antigen NY-ESO-1 induced, and is this associated with demethylation of their promoter regions?
b) does DAC alone vs. with VPA or ATRA induce DNA hypo- or hypermethylation in the leukemic blasts (comparison to normal, "bystander" T cells)?

The long-term research goal is a better understanding of the mechanisms of action of epigenetically active agents, including those not directly linked to DNA hypomethylation and chromatin modifications.

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  • Michael Lübbert

    University of Freiburg Medical Center
    Hugstetter Str 55
    D-79106 Freiburg, Germany
    Phone +49-761-270-32790
    Fax +49-761-270-36970




    Nadja Blagitko-Dorfs
    Pascal Schlosser
    Gabriele Greve
    Tobias Bauer
    Gregor Klaus
    Ruhtraud Ziegler