Targeting chromatin complexes in fusion protein-driven malignancies

Recurrent chromosomal rearrangements leading to the generation of oncogenic fusion proteins are a common feature of many cancers. These aberrations are particularly prevalent in sarcomas and haematopoietic malignancies and frequently involve genes required for chromatin regulation and transcriptional control. In many cases, these fusion proteins are thought to be the primary driver of cancer development, altering chromatin dynamics to initiate oncogenic gene expression programmes. In recent years, mechanistic insights into the underlying molecular functions of a number of these oncogenic fusion proteins have been discovered. These insights have allowed the design of mechanistically anchored therapeutic approaches promising substantial treatment advances. In this Review, we discuss how our understanding of fusion protein function is informing therapeutic innovations and illuminating mechanisms of chromatin and transcriptional regulation in cancer and normal cells.