Epigenomic Regulation of Stem and Progenitor Cells in Acute Myeloid Leukemias

• Applicant: Dr. Maximilian Christopeit
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193617394

Multiparameter fluorescence activated cell sorting enabled the separation of leukemic stem cells (LSC) from progenitor cells to identify genetic events which only lead to malignant transformation at specific stages of differentiation. Epigenetic events, as for example DNA methylation of promoter regions, coding sequences, introns and intergenic regions, happening exclusively on the stem and progenitor cell level and leading to malignant transformation or genetic instability have not been characterized in detail. This is especially interesting as „epigenetic therapy“ by inhibiting the methyltransferase Dnmt1 has shown first antineoplastic effects. Patients with -7/7q- acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) both show a dismal prognosis when treated conventionally and with allogeneic stem cell transplantation. Surprisingly, they fare quite well when treated with the inhibitor of the methyltransferase Dnmt1, 5-Azacytidine. This grant application aims at identifying hypomethylated regions in purely sorted LSCs from patients with MDS or AML carrying a monosomy 7 or a deletion of the long arm of chromosome 7 (-7/7q-) by means of array technology and next generation sequencing. Functional consequences of hypomethylation of one transcription factor on gene and protein expression will be assayed in primary hematopoietic stem and progenitor cells from healthy donors as well as in NOD-SCID-IL2RЎ-null (NOG) mice. Furthermore, underlying mechanisms will be characterized biochemically in primary cells and in the cell line Mono7. A more profound understanding of the mechanisms „epigenetic therapy“ exerts and the causes of its failure will lead to more efficient therapy against MDS and AML.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Ulrich G. Steidl