THE FOCUS of our research is on understanding the fundamental biology of developing myeloid white blood cells and how these developmental processes go awry in blood cancers. Our work is particularly focused in the epigenetic processes involved with blood cell fate specification. Subtle perturbation to these processes are the founding event in leukemia development, often occurring years to decades before disease develops. Through studying these early events in leukemia development, we aim to develop strategies to intervene early in the course of disease and to more effectively treat individuals with advanced disease.
Epigenetic Mechanisms in Preleukemia
A fundamental area of interest in our group is understanding the mechanisms of mutations that occur early during leukemia development. We have a particular interest in mutations in the chromatin regulator Additional Sex Combs-Like 1 (ASXL1). Mutations in this gene can occur in individuals with normal blood counts as well as in more advanced disease. Wherever ASXL1 mutations are found, they are associated with a high risk of progression and poor treatment responses. Using mouse models, cell lines and primary patient samples, we investigate the role of ASXL1 in myeloid development and how this is impacted by oncogenic mutations. Our work implicates that ASXL1 regulates the activity of the basal transcriptional apparatus, modulating global gene expression. These findings have implications for how we might approach therapeutic targeting of mutant ASXL1.
Role of Mutation Order in Leukemia Development
Mutations in acute myeloid leukemia (AML) can be functionally separated into two distinct classes. Class I mutations activate signaling pathways and drive proliferation while Class II mutations block differentiation. Sequencing studies suggested that Class II mutations tend to occur prior to Class I mutations, however we lacked a mechanistic explanation for why this occurs. We therefore developed a novel system in which mutation order can be temporally controlled in vitro and in vivo. Using this system, we demonstrated that Class II mutations in the transcription factor CEBPA must occur prior to Class I mutations in the growth factor receptor CSF3R in order for leukemia to develop. Mutations in CEBPA alter the epigenetic landscape, disabling key enhancers needed for normal differentiation. However, this can only occur when these mutations occur as the initiating event. These studies provide the first mechanistic insight into why Class II mutations occur earlier than Class I mutations in leukemia development.
Combination Kinase and Epigenetic Inhibitor Therapy for Acute Myeloid Leukemia
Kinase inhibitor therapy can produce dramatic responses in AML, with marked reductions in disease burden. However, these responses are short lived with the inevitable development of resistance. A key driver of resistance is the failure of such drugs to clear minimal residual disease, a persistent malignant population from which resistant clones can arise. Given the epigenetic nature of AML, we are interested in combining kinase inhibitors with drugs targeting the leukemic epigenome. In particular, we have found that inhibitors of LSD1 potentiate the activity of JAK inhibitors in JAK/STAT driven AML. We are interested in whether this approach may be generalizable to other forms of AML.
Funding for our work generously provided by
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The American Cancer Society
The American Society for Hematology AstraZeneca Blueprint Medicines The Collins Medical Trust The Knight Cancer Institute Center for Early Detection Advanced Research (CEDAR) Edward P. Evans Foundation Gilead Sciences International Alliance for Cancer Early Detection (ACED) The Kuni Foundation The National Institute of Health The National Cancer Institute The Medical Research Foundation |
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