Caner Saygin, MD
Assistant Professor, Department of Medicine, University of Chicago
Decoding the evolution of TP53-mutant acute leukemias
how do patients with tp53-mutations in their blood cells develop acute leukemia?
As scientists have come to better understand leukemias, several targeted therapies and immune-based therapies have improved survival outcomes of patients with acute leukemias. However, 10-20% of all acute leukemias have TP53 mutations; these TP53-mutated leukemias respond poorly to current therapies and are characterized by higher rates of relapse and much poorer survival. Moreover, TP53 mutations are more common in therapy-related leukemias, which develop after exposure to chemotherapy or radiation therapy used to treat an earlier cancer. In patients with therapy-related leukemias, TP53 mutated clones can be detected years before the emergence of their leukemia. The presence of mutations in blood cells, when these is no cancer yet, is called clonal hematopoiesis (CH) and CH is a well-known risk factor for the development of leukemias. However, the mechanisms regulating CH progression to TP53-mutant leukemias are still unknown.
Dr. Saygin plans to address this gap in our knowledge about how TP53 mutated clones progress from CH to acute leukemia. He will compare blood and bone marrow samples from patients with TP53-mutated acute leukemias and TP53-mutated CH without leukemia (individuals with the precursor condition) through single cell multiomics analysis, using a new method his lab has developed that combines DNA, protein, and RNA data obtained at the single cell level. This technology will enable Dr. Saygin’s lab to decipher the evolutionary patterns of different clones over time and to discover new mechanisms responsible for disease biology. He will also study the evolution of TP53-mutated leukemia in vivo, using a new mouse model developed in his lab. By providing new insights into the evolution of TP53-mutant leukemias, Dr. Saygin hopes to help prevent these fatal leukemias in high-risk individuals. In addition, he plans to identify new biomarkers to help stratify CH patients into high- and low-risk groups for leukemic progression. He also plans to identify new targets that can be exploited for the treatment of patients with TP53-mutant leukemias. Finally, as cancer patients are living longer with their disease, the incidence of TP53-mutated therapy-related leukemia will continue to increase and Dr. Saygin’s work will bring new perspectives on leukemia prevention in patients with CH, including patients who are being treated for primary solid tumors, better informing the treatment choices their doctors can offer.