Project Details
Projekt
Epigenetic, Genomic, and Functional Characterization of MLL-AF9 Rearranged Acute Myeloid Leukemia
Applicant
Professor Dr. Michael Kühn
Subject Area
Hematology, Oncology
Term
from 2012 to 2015
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 229644315
Rearrangements of the mixed-lineage leukemia (MLL) gene are associated with the development of acute leukemia, and a variety of translocation partners have been described to date. In acute myeloid leukemia (AML), the translocation t(9;11)(p22;q23), resulting in the MLL-AF9 fusion gene, is the most common genetic event involving MLL. The t(9;11) can be found in de novo as well as in therapy-related AML (t-AML). Recent data from murine MLL-AF9 models provide evidence that the H3K79 methyltransferase DOT1L is recruited to promoters of MLL target genes leading to unique aberrant methylation profiles and consecutively to altered HOX gene expression thereby contributing to leukemogenesis. In addition, de novo and t-AML with t(9;11) exhibit significant biological and clinical heterogeneity, and cooperating genetic events have been implicated underlying these heterogeneous phenotypes. Specific objectives of this proposal are therefore: (1) Characterization of genome-wide H3K79 methylation and DOT1L/H3K79me2-dependent gene expression in human MLL-AF9 rearranged de novo and t-AML samples. (2) Integrative analysis of large-scale genomic, transcriptional, epigenetic and mutational profiling screening data from human MLL-AF9 rearranged AML samples to identify cooperating lesions and candidate genes. (3) Functional characterization of candidate genes identified in objective 2 using xenotransplantation experiments and a murine MLL-AF9 leukemia model. The results of this research project will contribute to a better understanding of MLL-AF9 rearranged AML and should provide important data for the development of novel therapeutic approaches.
DFG Programme
Research Fellowships
International Connection
USA
