How does adaptation to stress drive clonal selection, evolution, and resistance in the blood system?
Blood stem cells are constantly tested by aging, inflammation, and cancer therapy. We study how the mutations that help cells survive that stress also let them outcompete their neighbors, evolve, and ultimately resist treatment, and how to turn that biology into new therapies for blood cancers such as myelodysplastic syndrome and leukemia.
Our Approach to Science
We combine human genetics, mechanistic biology, and drug discovery in a single group, moving between patient samples, experimental models, and chemistry. That lets us follow a question from a mutation first observed in patients all the way to a candidate therapy. The themes below are facets of one central question: how cells adapt to stress, and what that adaptation costs us in the clinic.
Research Themes
Sensing and surviving cellular stress
Every blood stem cell has to manage damage to its DNA. We study the genes that control this response, particularly PPM1D and TP53, and how mutations in them change the way a cell handles stress. We generated the first conditional mouse models of Ppm1d and used them to show that altered PPM1D activity rewires DNA damage signaling and lets cells expand under genotoxic stress. This work defines the mechanistic starting point for everything else the lab studies: how a survival advantage at the level of a single cell is first established.
Selection and evolution under pressure
The mutations that accumulate in blood are not random. They reflect the specific pressures a cell experiences, including aging, inflammation, and cancer treatment. By combining analyses of large patient cohorts with experimental models, we have shown that exposure to genotoxic therapy strongly favors the expansion of clones carrying DNA damage response mutations such as PPM1D and TP53. We study the rules that govern which clones win, in order to understand who is at risk of progressing from clonal hematopoiesis to overt malignancy, and when.
Mechanisms of therapeutic resistance
The same adaptations that help a cell survive stress are often what make a blood cancer hard to treat. This is a central focus of the lab: understanding why disease persists and returns after therapy. We have shown that PPM1D mutations confer resistance to chemotherapy, and that resistance can be reversed by inhibiting PPM1D, directly linking a stress-response mutation to a treatable vulnerability. We also study how leukemia stem cells persist through treatment and how non-genetic differences between cells shape which ones survive, with the goal of finding ways to overcome resistance rather than work around it.
From mechanism to therapy
We translate these discoveries into potential treatments inside the same lab. We built an integrated drug-discovery platform spanning structural modeling, saturation mutagenesis, high-throughput small-molecule screening, medicinal chemistry, and quantitative functional assays, and used it to develop allosteric inhibitors of the phosphatase PPM1D. To test candidates in disease-relevant settings, we use conditional mouse models, patient-derived xenograft models of normal and malignant hematopoiesis, and genome editing of primary human stem and progenitor cells. This is where the lab's biology becomes a path toward new therapies for patients.
Clonal hematopoiesis beyond cancer
Mutations that expand blood stem cell clones can also reprogram the immune system. We study how clonal hematopoiesis shapes inflammation and immune-mediated disease, from chronic lung disease to the severity of infections like COVID-19 and to inflammatory toxicities of cellular therapy. This direction extends the lab's central interest in somatic mutation beyond cancer, into the broader question of how the genetic makeup of blood influences health.