Investigating the Role of ASXL1 Mutations in CALR-mutated Myeloproliferative Neoplasms
Frederike Kramer
PhDBrigham and Women’s Hospital
Project Term: July 1, 2022 - June 30, 2025
My research focuses on myeloproliferative neoplasms (MPN) and the mutations that drive the progression of these blood cancers. Currently, I am investigating mutations in the gene ASXL1, which are associated with a poor prognosis. I am using mouse models and patient-derived cells to determine how ASXL1 mutations mediate epigenetic changes in MPN. My goal is to identify ways of targeting the pathological mechanisms caused by ASXL1 mutation, resulting in new treatment strategies for patients.
Myeloproliferative neoplasms (MPN) are a group of blood cancers that are caused by one of three gene mutations (JAK2, CALR or MPL) in hematopoietic stem cells. Especially as these cancers progress to more advanced stages, patients often acquire additional mutations. One of the frequently co-occurring mutations is found in the gene ASXL1. Mutations in ASXL1 have a special significance for MPN patients, as they are associated with a poor prognosis and adverse effects. In previous work, I have used mice to generate a model system that reflects the effects of ASXL1 mutations in patients. In these mice, both the driver mutation in Calr as well as the mutation in Asxl1 are present. These mice have a more severe disease compared to mice which harbor the Calr mutation alone. Given the important role of ASXL1 mutations in MPN patients, I will investigate how these mutations cooperate with the MPN driver mutation in CALR to promote disease progression. My first aim is to study how Asxl1 mutations influence the way Calr-mutant hematopoietic cells differentiate and proliferate, which are attributes that are often altered in blood cancers. Secondly, I will identify changes in histones in the Calr-Asxl1-mutant mouse model. Histones are packaging proteins that form complexes with the DNA. The way histones are modified impacts how genes within the DNA are read, which is referred to as epigenetics. ASXL1 is a so-called epigenetic regulator, since the protein that is produced based on the ASXL1 gene is directly involved in helping histone-modifying enzymes to bind to histones. The way ASXL1 interacts with other enzymes is different in mutated vs. non-mutated ASXL1, and consequently I expect histone modifications to be altered in Calr-Asxl1-mutant cells. Lastly, I will determine how exactly mutant ASXL1 mediates epigenetic changes by analyzing which enzymes ASXL1 interacts with. For this I will use patient-derived cells that are reprogrammed to acquire stem cell-like features (induced pluripotent stem cells). Since I have shown that mice which have both the Calr and Asxl1 mutation have a more aggressive cancer, I expect to find the underlying reason in altered ASXL1 interactions in double mutant cells. The goal of my research is to establish the molecular mechanisms that are responsible for the adverse effects of ASXL1 mutations in MPN patients. The results will help to identify new therapeutic targets that address the negative impact of ASXL1 mutations in MPN patients.