Acute Myeloid Leukemia (AML) is a frequent cancer of the blood system, which more than 80% of patients do not survive for more than 5 years after diagnosis. Straightforward clinical decisions are complicated by the immense genetic complexity of AML and by the lack of personalized treatment options. Many patients exhibit chromosomal aberrations giving rise to fusion proteins, which act as strong driver oncogenes. The chromosomal rearrangements are grouped into “Multi-Partner Translocation” (MPT) families, with one specific gene fused to a variety of recipients. This modular architecture makes MPT families interesting subjects for comparative studies of oncogenic mechanisms. The three most common MPT families in adult and pediatric AML represent translocations of the MLL, RUNX1 and NUP98 genes, all featuring more than 20 members. Despite their high clinical significance, the molecular mechanisms that underlie oncogenic transformation remain unknown for the majority of fusion proteins. Furthermore, it is unclear if transforming mechanisms are conserved within and across different MPT families.
In this project, we aim to delineate critical common components of oncogenic mechanisms in AML driven by MPT families through a comparative analysis of 20 MLL-, RUNX1- and NUP98-fusion proteins. First, we will describe how fusion proteins interact with their partner proteins and how they regulate the expression of target genes. Second, we will identify critical components within the fusion-protein-dependent regulatory landscapes by systematic loss-of-function screening. High-confidence candidates will be further analysed in detail in AML cells via different molecular approaches.
This project will contribute to the clarification of molecular mechanisms underlying fusion-protein-dependent oncogenic transformation. We are convinced that knowledge about the oncogenic mechanisms can be translated into clinical approaches for better patient management strategies for AML patients.
