Revisiting splicing factor mutations in MDS/AML – delving deep and wide

Myelodysplastic syndromes (MDS) are a group of blood cancers characterized by the bone marrow's failure to produce mature, functional blood cells. This results in low blood cell counts, abnormal cell morphology, and progression to acute myeloid leukemia (AML), a highly aggressive form of blood cancer with poor survival rates. MDS affects over 20,000 individuals annually and primarily impacts older adults, with a median age at diagnosis of 70 years. The only curative option, hematopoietic stem cell transplantation, is often not possible for elderly patients due to its toxicities, creating an urgent need for alternative treatments.

Mutations in splicing factor (SF) proteins, discovered over a decade ago, occur in over 50% of patients with MDS and secondary AML, but as of today there are no effective targeted treatments. SF proteins, such as SRSF2 and U2AF1, are essential for RNA splicing, a process that removes non-coding RNA segments to produce mature RNA for protein production. Mutations in these SF proteins lead to improper splicing and, consequently, abnormal cellular function, clonal outgrowth, and hematopoietic failure. While we understand more and more how these mutations cause abnormal splicing, it is still unclear how they allow cells to take over the bone marrow space. We also do not yet understand how these mutations affect the function of the many other proteins required to process RNA for efficient production of the exact type, number and quantity of proteins needed in a cell. Better understanding of these complex processes may highlight possible targets for treatment.

To bridge this gap, my lab uses state-of-the-art RNA mapping technologies to study splicing factor mutations at single-nucleotide resolution, providing a detailed view of how these mutations disrupt RNA binding and processing. So far we have uncovered that that SF mutations alter RNA binding in sequence-specific ways resulting in abnormal splicing. However, abnormal binding does not lead to a single outcome suggesting that interactions with other RNA processing factors may also be disrupted. Here I propose to understand these complex interactions by creating comprehensive protein-RNA interaction maps along the entire journey of an RNA.

My ultimate goal is to provide the scientific and clinical communities with new targets and pathways for therapeutic discovery and development, enhancing efficacy and reducing toxicity of treatments for splicing factor mutant MDS and AML.