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
We have a long-standing interest in CSF3R, which is the receptor for a cytokine that promotes the production of neutrophils. CSF3R mutations are a molecular hallmark of chronic neutrophilic leukemia (CNL), where they occur in greater than 80% of patients. These same mutations occur more rarely in acute myeloid leukemia (AML), which is characterized by immature myeloid blasts rather than the mature cells found in CNL. In these diseases, very different partner mutations occur alongside mutated CSF3R. We are using a multi-pronged approach to understand how these mutations cooperate to distinct cellular phenotypes in vitro and in vivo. These include, CRISPR/Cas9, mouse hematapoeic Colony Forming Unit (CFU) Assays, myeloid differentiation models and bone marrow transplants. Finally, we are utilizing a high-throughput screening platform to identify therapeutic targets in an unbiased manner. These models allow us to recapitulate clinical phenotypes in a simpler system, and understand how oncogenic mutations act in concert to produce disease.
Elucidating the complex molecular evolution of leukemia
We are interested in understanding the evolution and mutational complexity of myeloid leukemia from a subclinical state to myeloproliferative neoplasms to acute leukemia. Myeloid leukemias can comprise a complex clonal architecture that changes over time. To better understand the clonal complexity, we are developing methods to detect mutations at the single-cell level . We are investigating the importance of order of mutation acquisition using both in vitro and in vivo models. Through this multi-pronged approach, we hope to gain a deeper understanding of the complexity and evolution of leukemias to better guide our drug development efforts.
Protein glycosylation is becoming increasingly recognized as playing a critical role in the process of malignant transformation. Glycosylation, the addition of carbohydrate groups (sugars) to proteins, can have a major effect on protein folding, structure, and functional interactions. In cancer, the addition of certain sugars to sites of glycosylation, truncation of O-glycan structures, and altered carbohydrate branching can have a profound effect on tumorigenesis and metastasis. We are working to understand the way that glycosylation-altering mutations in CSF3R activate oncogenic signaling and to investigate the potential for other mutations in sites of glycosylation to promote tumorigenesis.