Advances in sequencing technologies have yielded a wealth of genomic data that promise to revolutionize the care of cancer patients. Fundamental to the realization of this promise is the distillation of massive quantities of correlative genomic data into a mechanistic understanding of disease. The focus of our lab is to utilize model systems to explore the cellular mechanisms of novel oncogenic mutations and how these mutations cooperate in disease biology. This work will allow for a mechanistic, as opposed to phenotypic, categorization of cancer, facilitating an improved understanding of oncogenesis and identification of novel drug targets for personalized medicine.
Combinatorial genomics of myeloid malignancies
Mutations in CSF3R—the cytokine receptor that drives neutrophil production—are the molecular hallmark of chronic neutrophilic leukemia (CNL), where they occur in greater than 80% of patients. These same mutations also occur in acute myeloid leukemia, which is characterized by immature myeloid blasts rather than the mature cells found in CNL. In these diseases, very different partner mutations occur alongside mutant CSF3R. We are using single-cell, epigenetic, and transcriptomic techniques in conjunction with functional studies to understand how these mutations cooperate to drive distinct disease phenotypes.
CSF3R activation and signaling
The most common leukemia-associated mutations in CSF3R eliminate sites of receptor glycosylation. We are working to understand the way that these glycosylation-altering mutations promote ligand-independent receptor activation to drive oncogenesis. We are also using proteomic approaches to identify novel mediators of receptor signaling, trafficking and degradation.
Understanding the molecular evolution of leukemia
We are interested in understanding the evolution of myeloid leukemia from a subclinical state to myeloproliferative neoplasms to acute leukemia. This evolution is associated with the acquisition of mutations over time. Some of these mutations arise early in disease development, while others occur as late events. We are working to uncover the mechanistic basis for this stereotypic order of mutation acquisition and to understand the impact of mutation order on disease pathobiology.
Targeting epigenetic dysfunction in myeloid leukemia
A hallmark of myeloid malignancies is dysregulation of the epigenome. We are using low-input epigenetic techniques in murine models and human leukemia samples to understand the epigenetic dysfunction associated with particular disease subtypes. We are also using these tools to understanding the dynamic response of myeloid leukemia to epigenetic modulatory agents. Our goal is to develop effective combinatorial therapeutic strategies to better treat these deadly malignancies.