Advanced Medical Scientist-Programm

Thema: "Unlocking the curative potential of ATRA in non-APL AML: Identification of the mechanisms underlying repression of retinoic acid receptor activity by aberrant lysine modification."

Zusammenfassung:
The combination of a high median age at the time of diagnosis and a lack in targeted therapies makes acute myeloid leukemia (AML) one of the deadliest cancers. AML is characterized by a block in hematopoietic differentiation. One subtype of AML, acute promyelocytic leukemia (APL) can be cured using the retinoic acid receptor (RAR) agonist all-trans-retinoic acid (ATRA), enforcing myeloid differentiation. Non-APL AML cells are resistant to ATRA. This is at least in part due to downstream epigenetic deregulation. We found the lysine demethylase LSD1 and the acetyltransferase GCN5 to block ATRA induced differentiation in non-APL AML cells. Combination treatment with ATRA and inhibitors against LSD1 (GSK-LSD1) and GCN5 (MB3) triggered myeloid differentiation in AML cell lines and patients’ blasts. In this project we will analyze cells from a large cohort of patients aiming to identify cytogenetic, genetic and epigenetic factors that are responsible and therefore predictive for successful targeted treatment. Furthermore, we will investigate the in vivo effectiveness of MB3, the only available specific inhibitor of GCN5. To elucidate the interplay between RAR, LSD1 and GCN5 in AML we will map their chromatin binding sites and binding pattern changes using conventional and novel UV-Laser based chromatin immunoprecipitation technology. We believe that this project, combining translational and focused basic research, will greatly contribute to the development of therapies targeting the differentiation blockage in non-APL AML.