ABSTRACT Due to an ever-increasing number of cancer survivors, myeloid neoplasms associated with chemotherapy and/or ionizing radiation are a significant concern for public health. Clinical data indicate that the outcome for patients with therapy-related myeloid neoplasms (t-MNs) is poor, with a 5-year survival of 10%. The unfavorable response of t-MNs to standard cancer therapies is largely due to mutations in the tumor suppressor p53. It has been demonstrated that p53 mutant t-MNs are developed through the expansion of rare tumor-initiating cells harboring pre-existing p53 mutations. Therefore, the overall goal of this project is to prevent the development of p53 mutant t-MNs by inhibiting the expansion of tumor-initiating cells and/or by selectively killing tumor-initiating cells at the premalignant stage. To selectively target p53 mutant cells, we will use APR-246, a small molecule drug in clinical trials that reactivates mutant p53 protein by restoring wild-type p53 conformation and function. We hypothesize that treatment with APR-246 will prevent the genotoxic stress-induced expansion of p53 mutant HSPCs and selectively kill p53 mutant HSPCs that have expanded after genotoxic therapies. We will test this hypothesis using a novel mouse model that we have developed in which rare HSPCs expressing a p53R172H mutation undergo cell expansion after exposure to total-body irradiation in two specific aims: Aim 1 – Evaluate the impact of APR-246 treatment during total-body irradiation on the expansion of p53 mutant HSPCs and Aim 2 – Examine the effect of APR-246 plus azacitidine on killing p53 mutant HSPCs that have expanded after total-body irradiation. We anticipate that the outcomes from this proof-of-concept R03 grant will generate reproducible data that support further investigation of utilizing APR-246 or other mutant p53 activators to minimize the risk of t-MNs in cancer patients who show clonal hematopoiesis of mutations in the tumor suppressor p53.