Redefining the role of RNA binding by the MLL1 (KMT2A) complex in leukemia

Dysfunction of the MLL1 protein complex is a common cause of leukemia, accounting for the most frequent mutation in early childhood leukemias marked by no effective standard of care. In these leukemias, the MLL complex activates genes that keep immune cells growing; the inability to turn off these genes causes this class of leukemias. Precisely how the MLL1 complex finds these target genes is not well understood at the molecular level; there is an RNA molecule called HOTTIP which is transcribed right next to the key genes for leukemogenesis and is essential to recruiting the MLL1 complex. Several labs have identified one of the protein parts of the MLL1 complex as the point of contact to HOTTIP. However, Dr. Ruthenburg has developed strong evidence that this model is incorrect: that this protein has no specificity for HOTTIP so it cannot guide the MLL1 complex to these key leukemia target genes
because they would be indistinguishable from thousands of other possible binding places in the genome. Instead, Dr. Ruthenberg has identified a different protein in the complex, RBBP5, that can specifically recognize HOTTIP. He will use his Fletcher Scholars Award to attempt to define that which has remained elusive for more than a decade due to flawed prior studies: a detailed understanding of how HOTTIP RNA impacts the MLL1 complex mechanism and how it functions in the development of
leukemia. He will pursue a set of experiments to define how HOTTIP RNA impacts the MLL1 complex in leukemia and to show whether these RNA-MLL1 complex interactions can be druggable by inhibitor molecules, hoping to pave the way for new therapeutics needed to treat these deadly leukemias.