Therapeutic targeting of a niche-originating pathway driving TP53-mutant AML

Acute myeloid leukemia (AML), the most common blood cancer in adults arises through serial accumulation of genetic alterations in blood forming cells that gradually expand leading to AML. Among the most aggressive types of the disease is TP53m-AML, characterized by mutations in the gene encoding for the P53 protein that controls cell growth and suppresses cancer. Patients with TP53 mutations have poor prognosis with a 5-year overall survival as low as 2%. Response to standard chemotherapy or bone marrow (BM) transplantation is very low or short-lived underlining the urgent, unmet medical need. However, the mechanisms that favor the expansion of blood cells carrying TP53 mutations are unknown. Our observations in leukemic mice and AML patients indicate a correlation between TP53m-AML and deregulation in the surrounding bone forming cells in the BM niche. Interestingly, deregulation in bone cells and low frequency TP53 mutations in blood cells increase with aging, in healthy subjects, suggesting that niche deregulation may promote TP53m cell expansion, leading to AML. In this study, we will characterize and track the molecular and cellular events occurring during TP53m-AML onset and progression in mice and assess the therapeutic efficacy of blocking them in patient-derived cells. This work has the potential to establish a novel mechanism for TP53m-AML progression, that may also apply to other types of blood cancers and provide a potential new therapeutic approach for TP53m-AML.