Varun K. Narendra, M.D., Ph.D.
2022 Funding recipient
Interrogating and Exploiting TP53 alterations in Myelodysplastic Syndrome
EvansMDS Young Investigator Award
Myelodysplastic syndrome (MDS) is a cancer of blood-forming stem cells, wherein genetic mutations arise in these cells, and lead to defective production of cell types of the blood, including immune cells, red blood cells and platelets. To date, a broad set of genetic mutations have been identified as causative in MDS. However, certain mutations, including mutations in a gene called TP53, are associated with particularly poor clinical outcomes, including more frequent progression to acute myeloid leukemia (AML). Moreover, current treatments for TP53 mutant MDS are minimally effective, and there is a pressing need for novel therapies. Future therapies should ideally target the TP53 gene mutation itself, as it lies at the root of the disease.
TP53 is classically known as a tumor suppressor gene, meaning it functions to suppress, i.e., prevent, cancer formation. Mutations in TP53 can inactivate this function, thereby “releasing the break” on cell growth. In addition, there is growing evidence that certain TP53 mutations may have oncogenic effects, akin to “pushing down on the gas pedal”, leading to uncontrolled growth of MDS cells. In this proposal, we outline an approach to systematically identify TP53 mutations that have oncogenic properties. Our approach uses novel genetic manipulation strategies to simultaneously study the effects of many different mutations within TP53 simultaneously within the blood-forming stem cells of just a single mouse. Having identified specific mutations that have oncogenic functions, we then dig deeper. We outline methods to identify how certain mutations in TP53 function as oncogenes, particularly in the context of radiation and chemotherapy exposure, two external stresses that are common risk factors for developing TP53-mutant MDS. Armed with this knowledge, we then design assays to figure out how to block TP53 oncogenic function, and thereby prevent the development of MDS.