Cytoplasmic transcription factor sequestration drives the pathogenesis of a rearranged leukemia

The oncofusion genes created by chromosomal translocations frequently drive hematological malignancies. In general, the chimeric proteins resulting from these oncofusions initiate and drive cancer pathogenesis by disrupting specific cellular mechanisms regulating patterns of gene expression. For example, translocations involving chromosome 11q23, which are among the most common found in pediatric leukemias, create fusions of the MLL-encoding gene KMT2A with any of a large number of genes on other chromosomes. It was mechanistically demonstrated that several of these seemingly unrelated oncofusion partners encode subunits of an RNA polymerase II elongation factor now known as the super elongation complex (SEC) (1). Therefore, translocations involving chromosome 11q23 drive cancer by creating chimeric fusions of MLL to SEC subunits, disrupting SEC’s role in transcriptional elongation checkpoint control. In other cases, oncofusion protein chimeras may also affect transcription factor stability, alter patterns of chromatin binding, hijack enhancers, or otherwise disrupt transcriptional regulatory mechanisms. In an elegant study from Tim Ley’s laboratory published recently in the JCI, Day et al. (2) defined another mechanism by which translocations can cause cancer, demonstrating that the CBFB::MYH1 oncofusion protein chimera drives oncogenesis by sequestering the transcription factor Runx1 in the cytoplasm.