Understanding and Targeting Mutant p53 in Myelodysplastic Syndromes
Abstract
Active duty military members are frequently exposed to ionizing irradiation, chemicals, infectious agents, and/or environmental carcinogens. These exposures can cause mutations in blood stem cells that lead to blood disorders such as myelodysplastic syndromes (MDS). As expected, there are increasing numbers of Gulf War Veterans returning from theater with irradiation- or toxin exposure-related MDS. MDS are acquired bone marrow failure syndromes that occur in the elderly and affect between 20,000 and 45,000 people each year in the United States. In addition, MDS patients are at an increased risk of developing leukemia. The clinical outcome of MDS patients is still very poor, despite progress in treatment approaches. Previous studies found mutations in a tumor suppressor gene (TP53) in 10% of MDS cases and in 20–30% of secondary MDS arising after exposure to radiation or other toxic agents. As TP53 mutations are associated with short survival and drug resistance in patients with MDS, the goal of this study is to understand the role of these TP53 mutations in MDS in order to develop novel treatments for MDS patients. MDS are bone marrow failure syndromes initiated from a small population of mutated hematopoietic stem cells called MDS stem cells. The inflammasome is a protein complex that is important the release of inflammatory growth factors (inflammatory cytokines) by MDS stem cells. We found that the inflammasome is activated in MDS stem cells expressing mutant p53, and these cells release more inflammatory cytokines to impair normal stem cell function. In addition, there is another protein complex, called the spliceosome, which is the machinery for RNA splicing. If mRNAs in cells are not properly spliced, people may develop diseases such as MDS. Recently, mutations in spliceosome genes were found in 60% of MDS patients. We found that the expression of spliceosome genes were downregulated in MDS stem cells expressing mutant p53. Further, we observed that mRNAs are not properly spliced in MDS stem cells with mutant p53. Based on these findings, we hypothesize that mutant p53 proteins activate the inflammasome and alter RNA splicing, leading to the formation of MDS stem cells. We will test drugs targeting the inflammasome and spliceosome on mouse and human MDS stem cells with mutant p53. We anticipate that these drugs will kill drug-resistant MDS stem cells. Upon completion of this research, we expect to establish both the inflammasome and spliceosome as new druggable targets for clinical trials for MDS patients. Successful completion of these studies would be expected to have an important positive impact on military personnel, Veterans and their family members. In addition, the proposed work will facilitate the clinical application of inflammasome and spliceosome inhibitors in treating military personnel, Veterans, and their dependents with MDS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810265
Entities
People
- Yan Y Liu
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army