Enhancer hijacking in acute myeloid leukemia

Recurrent deletions in cancer genomes overlap with the chromosomal locations of tumor-suppressor genes. Knudson's two-hit hypothesis has successfully guided cancer biologists for the past fifty years in the identification of such tumor-suppressor genes. However, in many cases monoallelic loss can only explain haploinsufficiency of tumor-suppressor genes. Preliminary work in the division indicates that altered chromosome topology and epigenetic gene regulation can also affected by deletions, resulting in the activation of oncogenes located outside of the deleted segment.

We aim to establish a novel paradigm in interpreting (epi)genomic data in cancer. We hypothesize that oncogene activation, in concert with haploinsufficient tumor-suppressor genes, deregulated because of a single genetic event, could lead to the discovery of novel intertwined oncogenic pathways.

Using acute myeloid leukemia as a model, we aim:

• to reveal oncogene activation through novel molecular pathways in cases carrying deletions of 5q and 7q by molecular sequencing-based profiling and to validate the requirement of the novel oncogene(s) for leukemic growth.
• to determine the molecular mechanisms resulting from oncogene overexpression and to test the accelerated tumorigenesis dependent on haploinsufficient tumor suppressor genes.
• to determine the contribution of oncogene activation through structural variation in combination with haploinsufficiency in a pan-cancer setting.