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.


  • Hackanson B, Rimmele L, Benkißer M, Abdelkarim M, Fliegauf M, Jung M, Lübbert M.(2012). HDAC6 as a target for antileukemic drugs in acute myeloid leukemia. Leuk Res. [Epub ahead of print] PMID:22464548

  • Duque-Afonso J, Berg T, Heidenreich O, Lübbert M. (2011). The HDAC class I specific inhibitor Entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO. Oncogene 30:3062-72. PMID:21577204

  • Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jäger E, Lübbert M. (2010). The DNA demethylating agent 5-aza-2'-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk. Res. 34:899-905. PMID:20381863

  • Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, Plass C, Niemeyer CM, Lübbert M. (2009). The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on gene expression in acute myeloid leukemia cells. Leukemia 23:1019-28. PMID:19194470

  • Claus R, Hackanson B, Poetsch AR, Zucknick M, Sonnet M, Blagitko-Dorfs N, Hiller J, Wilop S, Brümmendorf TH, Galm O, Platzbecker U, Byrd JC, Döhner K, Döhner H, Lübbert M, Plass C. Quantitative analyses of DAPK1 methylation in AML and MDS. Int J Cancer, [Epub ahead of print]. PMID:21918973

  • Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U, Kuendgen A, Rethwisch V, Ganser A, Platzbecker U, Galm O, Brugger W, Heil G, Hackanson B, Deschler B, Döhner K, Hagemeijer A, Wijermans PW, Döhner H. (2012). A multicenter phase II trial of continued Decitabine as first-line treatment of older AML patients judged unfit for induction chemotherapy. Haematologica. PMID:22058219


  • Michael Lübbert


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


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