Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

DNA methylation control of myeloid leukemia stem cell genes


There is increasing evidence that apart from the rapidly proliferating, aggressive cancer cells, there are cancer stem cells (CSCs) that are able to escape conventional cancer therapy and cause disease relapses. They have a lot in common with normal stem cells, their self-renewal, long-term survival and differentiation potential. It is not known, how these CSCs develop. To answer this question is a main objective of our research.
DNMT1 is a DNA-methyltransferase that is responsible for the maintenance of methylation marks on the DNA. It is likely that the inheritable methylation marks have influence on the cellular fate by regulation of cell-type specific gene expression. In our previous work we could show that hematopoietic stem cells (HSCs) as well as leukemic stem cells (LSCs) have impaired self-renewal when they are transformed by a hypomorphic DNMT1 allele combined with a null allele, pointing to reduced ‘stemness’. Furthermore the hypomethylation led to a lower expression of stem cell genes and lymphoid genes in HSCs as well as to an increased synthesis of myeloerythroid gene products.

In our work we want to identify gene programs that are responsible for the development and maintenance of stem cell properties in LSC by analyzing gene expression profiles and methylation marks in hypomethylated LSCs. Uncovering these epigenetically controlled mechanisms could lead to the identification of targets for anti-cancer therapy with demethylating chemicals.
We are also exploring computational methods to improve the predictions of miRNA regulatory actions of the epigenetic modifications occurring along haematopoietic differentiation using network analysis. Initially we are integrating ChIP-seq data of transcription factors with miRNA target predictions to select biologically relevant miRNA targets for genes differentially expressed during differentiation and reprogramming.


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  • Frank Rosenbauer


    Institut for Molecular Tumorbiology - IMTB
    University of Münster
    Robert-Koch-Str 43
    D-48149 Münster, Germany
    Phone +49-251-83-55312
    Fax +49-251-83-55303


    Miguel Andrade-Navarro


    Max-Delbrück-Centrum for Molecular Medicine (MDC) Berlin-Buch
    Robert-Rössle-Str 10
    D-13125 Berlin, Germany
    Phone +49-30-94064250
    Fax +49-30-94064240

    Irina Savelyeva


    Institut for Molecular Tumorbiology - IMTB
    University of Münster
    Robert-Koch-Str 43
    D-48149 Münster, Germany
    Phone +49-251-83-51601
    Fax +49-251-83-55303

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