Understanding and Targeting Mutant p53 in Myelodysplastic Syndromes
Abstract
Myelodysplastic syndromes (MDS) are acquired bone marrow failure syndromes that affects between 20,000 and 45,000 people each year in the US. 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. 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, 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. Importantly, we found that human MDS cells with TP53 mutations are sensitive to inflammasome and spliceosome inhibitor treatment. Thus, mutant p53 proteins activate inflammasome and alter RNA splicing, leading to the formation of MDS stem cells. Upon completion of this research, we expect to establish both inflammasome and spliceosome as new druggable targets for clinical trials for MDS patients
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1114605
Entities
People
- Omar Abdel-Wahab
- Yan Y Liu
- Yunlong Liu