Projects
Cellular translation, nucleophosmin (NPM1), the ribosome and RNA biology. Discover how we are contributing to understanding leukemia and cancer…
Hundreds of labs around the globe are working to understand and cure leukemia. Each of them brings a unique approach to working on this disease. All of this work together is what will make a difference. Here are some of the areas that we are investing in right now.
NPM1 Biology and Function
NPM1 in hematopoesis and leukemia
The NPM1 gene is critical for normal blood development, a process termed hematopoiesis. We are interested in understanding how NPM1 is regulated during hematopoiesis and what are its critical functions that contribute to this process. To do this we are working to understand how individual NPM1 gene isoforms differ from one another in function, and how their balanced expression influences hematopoietic stem cell behavior. This will help us identify essential functions that are disrupted by genetic alteration and mutation to NPM1, which in turn promotes aberrant hematopoiesis leading to leukemia and cancer.
The Ribosome
Ribosome regulation and function
It is becoming increasingly clear that careful control of the ribosome is important for hematopoiesis, and abnormal ribosome function can result in diseases including bone marrow failure (BMF) disorders. We hope to discover how ribosome function is altered during aging of the hematopoietic system and how ribosome modification and function impacts leukemia development. This will be critically important in defining the impact of ribosome function on the hematopoietic stem cells (HSC) ability to respond to stress. One way that ribosome function can be regulated and fine-tuned is through post-transcriptional regulation of it’s ribosomal RNA (rRNA). Non-coding RNAs known as small nucleolar RNAs (snoRNA) can function to modify the ribosome in this way. A distinct class of snoRNAs known as C/D box snoRNAs act as guides for 2’-O-methylation (2’-O-Me or Nm) at specific positions on rRNA, whereby a methyl group is added to the 2′ hydroxyl of the ribose moiety of a nucleoside, producing a methoxy group. NPM1 can interact with a subset of C/D box snoRNAs and modify promote 2’-O-Me on specific positions on rRNA. Loss of NPM1s ability to interact with C/D box snoRNAs results in decreased 2’-O-Me at these positions on rRNA to promote aberrant hematopoiesis. Our work will help establish how NPM1 mediated ribosome methylation is altered in leukemia, and how this impacts the ability of hematopoietic to respond to stress.
Cell Signaling
Signaling pathways in translational control
Many genetic alterations that drive cancer promote altered and inappropriate signaling within the cell that enable the cell to grow unrestricted. We are striving to understand how NPM1 may regulate these pathways, how aberrant signaling impacts ribosome modification and function, and how abnormal ribosome function impacts cell signaling. Pathways that include the AKT/MTOR signalling pathway, RAS/MAPK signaling pathway, and unfolded protein response (UPR) or integrated stress response (ISR) signaling pathways directly effect the ribosome and cellular translation. Cancer therapies often directly target cell signalling pathways and altered cell signaling occurs in response to treatment. Understanding how key signaling pathways are controlled in normal hematopoiesis and leukemia will be vitally important for the development of new and improved therapeutic approaches to treat disease.
RNA Biology
Non-coding RNA in hematopoiesis
The role of non-coding RNAs in biology and disease has seen an explosion over the last 20 years. NPM1 binds a host of coding and non-coding RNAs, including C/D box snoRNAs that act to modify rRNA and regulate ribosome function in hematopoiesis. Indeed, the ribosome itself is macromolecule composed of non-coding ribosomal RNAs interweaved with ribosomal proteins. In addition, there are numerous long non-coding RNAs (lncRNA) and microRNAs (miRNA) that are deregulated in leukemia. As part of our studies on NPM1 and the ribosome we hope to further expand on what aspects of RNA biology are relevant in leukemia.
