The significance of dysregulated MEIS1 homeobox gene expression in the pathogenesis of acute myeloid leukemia (AML)

Coordinator:    Frau PD Dr. Michaela Feuring-Buske
Institution: Med. Klinik III, Klinikum Großhadern & KKG Leukämie, Helmholtz - Zentrum München
Leukemias cannot be cured despite modern therapies in the majority of patients. Therefore it is one of the pivotal goals to improve our understanding of the underlying mechanisms of leukemia development, thereby facilitating the development of improved therapeutic approaches. We know today that in leukemias aberrant regulation of certain regulatory factors are among the key events in disease development. This aberrant regulation can be caused by a critically elevated expression level of the factor, by the generation of fusion genes or by mutations of the factor. Examples for this are the aberrant expression of the MEIS1 protein, the AML1-ETO fusion gene and the NPM1 mutation, respectively. We furthermore know, that only the collaboration between different genetic alterations are sufficient to cause leukemia: e.g. the aberrant expression of MEIS1 is not able to cause leukemia. The aim of the project is to improve our understanding of the role of aberrant MEIS1 expression in leukemogenesis. In particular, the collaboration between MEIS1 and the AML1-ETO fusion gene or MEIS1 and NPM1 gene mutation will be analyzed. We previously showed that AML1-ETO strongly collaborates with MEIS1 in inducing murine leukemia. This work will be extended by analyzing a potential collaboration between MEIS1 and the NPM1 mutation, using a  NPM knock-out mouse model. The established murine leukemia models will be used to identify new therapeutic concepts for the treatment of these leukemia subtypes.
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