Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Contribution of disordered epigenetic regulation to the malignant phenotype of juvenile myelomonocytic leukemia

Aberrant DNA methylation contributes to the malignant phenotype in cancer including myeloproliferative neoplasms and myeloid leukemia. We previously described in juvenile myelomonocytic leukemia (JMML) a pattern of promoter hypermethylation that allowed the categorization of JMML cases into groups with no methylation (46% of patients), intermediate methylation (33%) or high methylation (21%).
Importantly, we found a significant association between high methylation and poor prognosis; among patients with hematopoietic stem cell transplantation, high methylation at diagnosis predicted a considerably increased risk of relapse.

We now propose to expand on these results by developing simplified methods for the quantitative determination of gene-specific and global DNA hypermethylation in JMML, by translating DNA methylation as a diagnostic and prognostic marker into the clinical management of JMML, by defining the high-methylation JMML phenotype in more detail and identifying novel methylation target genes, by investigating histone modification and chromatin conformation changes in JMML and describing their interaction with aberrant DNA methylation, and by differentially characterizing the leukemic progenitor cells in JMML cases with a hypermethylated and clinically refractory phenotype. We anticipate that these investigations will promote insight into epigenetic gene regulation in JMML and contribute to the understanding of resistance to therapy in this leukemia.

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  • 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 cancer gene expression in acute myeloid leukemia cells. Leukemia 23: 1019-1028. PMID:19194470

  • Furlan I, Batz C, Flotho C, Mohr B, Lübbert M, Suttorp M, Niemeyer CM. (2009). Intriguing response to azacitidine in a patient with juvenile myelomonocytic leukemia and monosomy 7. Blood 113: 2867-2868. PMID:19299654

  • Christian Flotho

    University of Freiburg Medical Center
    Mathildenstr 1
    D-79106 Freiburg, Germany
    Phone +49-761-2704628
    Fax +49-761-2704518




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