Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Genetic and epigenetic search for tumor suppressor genes on chromosome 7q in acute myeloid leukemia

Acute myeloid leukemia (AML) is one of the most frequent hematopoietic malignancies in adults. Therapies are stratified based on subgroups defined by the presence of recurrent chromosomal aberrations and/or gene mutations. Consequently, prognosis and clinical outcome of the disease is linked to the patterns of molecular and cytogenetic abnormalities.
Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias that are highly associated with myelodysplastic syndrome and AML, in particular with therapy-related or secondary MDS/AML.

Preliminary data obtained in our research consortium allowed the identification of three defined commonly deleted segments (CDS) on 7q suggesting the location and involvement of several tumor suppressor genes in AML. Furthermore, epigenetic profiling of these regions identified potential candidate genes silenced by both genetic and epigenetic alterations.

In this proposal we are providing the rational and experimental details to determine tumor suppressor function of one of these genes, ATXN7L1, localized in the CDR on chromosomal band 7q22.2. Our hypothesis for this proposal is that the deletion contributes to silencing of a dominantly acting tumour suppressor, whereby a “second hit” of the remaining allele is obtained by epigenetic inactivation and disruption of the gene’s function. This hypothesis will be tested using functional assays in cell culture systems and primary human AML cells with well defined genetic alterations.

  • 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

  • Krais AM, Park YJ, Plass C, Schmeiser HH. (2011). Determination of genomic 5-hydroxymethyl-2'-deoxycytidine in human DNA by capillary electrophoresis with laser induced fluorescence. Epigenetics 6:560-565. PMID:21593596

  • Olk-Batz C, Poetsch AR, Nöllke P, Claus R, Zucknick M, Sandrock I, Witte T, Strahm B, Hasle H, Zecca M, Stary J, Bergstraesser E, De Moerloose B, Trebo M, van den Heuvel-Eibrink MM, Wojcik D, Locatelli F, Plass C, Niemeyer CM, Flotho C. (2011). Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia (JMML) with poor outcome. Blood, 117:4871-4880. PMID:21406719

  • Park YJ, Claus R, Weichenhan D, Plass C. (2011). Genomie-wide epidenetic modifications in cancer (Review). Prog Drug Res, 67:25-49. PMID:21141723

  • Poetsch AR, Plass C. (2011). Transcriptional regulation by DNA methylation (Review). Cancer Treat Rev, 37 Suppl 1:S8-12. PMID:21601364

  • Christoph Plass

    German Cancer Research Center (DKFZ)
    Im Neuenheimer Feld 280
    D-69120 Heidelberg, Germany
    Phone +49-6221-423300
    Fax +49-6221-423359

    Hartmut Döhner

    University of Ulm Medical Center
    Albert-Einstein-Allee 23
    D-89081 Ulm, Germany
    Phone +49-731500-45501
    Fax +49-731-500-45505

    Konstanze Döhner

    University of Ulm Medical Center
    Albert-Einstein-Allee 23
    D-89081 Ulm, Germany
    Phone +49-731-50045543
    Fax +49-731-50045505




    Rainer Claus
    Anders Lindroth
    Daniel Lipka
    Anna Poetsch
    Maximilian Schmutz
    Miriam Sonnet
    Dieter Weichenhan
    Tania Witte