Molecular Evolution of Leukemias
We aim to understand the evolution of leukemia from a subclinical state to myeloproliferative neoplasm 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.
Our objectives are to uncover the mechanistic basis for this stereotypic order of mutation acquisition. As well as to understand how different oncogenic programs converge at the molecular level to produce difficult-to-treat disease.
Our objectives are to uncover the mechanistic basis for this stereotypic order of mutation acquisition. As well as to understand how different oncogenic programs converge at the molecular level to produce difficult-to-treat disease.
Epigenetic Dysfunction in Leukemia
A hallmark of myeloid malignancies is dysregulation of the epigenome to produced aberrant transcriptional states. A number of leukemia-associated gene mutations perturb transcriptional and epigenetic machinery to alter blood development.
We are focused on how mutations in the epigenetic regulators ASXL1 and SETBP1 drive leukemogenic programs. For these projects, we are using emerging low-input and single-cell profiling tools to interrogate murine models and human leukemia samples. Our computational team works collaboratively with wet lab biologists to analyze these data sets and also develops tools to help us better leverage these new technologies.
We are focused on how mutations in the epigenetic regulators ASXL1 and SETBP1 drive leukemogenic programs. For these projects, we are using emerging low-input and single-cell profiling tools to interrogate murine models and human leukemia samples. Our computational team works collaboratively with wet lab biologists to analyze these data sets and also develops tools to help us better leverage these new technologies.
Reversing Oncogenic Signaling
We previously discovered recurrent mutations in the cytokine receptor, CSF3R, in myeloproliferative neoplasms. These mutations amplify kinase signaling downstream of the receptor. This led to a successful clinical trial in which half of patients with CSF3R mutations responded to kinase inhibition.
We are working to develop therapies that better repress CSF3R-driven signaling to enable long-term remissions for patients with these malignancies. This project employs protein interaction and CRISPR screening to nominate new drug targets.
