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We are interested in the mechanisms that govern self-renewal and drug response in leukemia. Increasing evidence supports the concept that epigenetic mechanisms are critically important for leukemic growth and may often be responsible for treatment failure. We are especially interested in the role of the histone methylating protein complex Polycomb Repressive Complex 2 (PRC2) in leukemia. PRC2 is part of a complex network important in both cancerous growth and normal development. Both increased and decreased activity of PRC2 are associated with aggressive cancers in the bone marrow and in other organs. We think that the study of PRC2 will eventually help to develop less toxic and more efficient leukemia therapies.
Epigenetic mechanisms involve gene regulation with:
1. memory (over several cell divisions
or even over generations) and
2. no change in the DNA coding sequence
Confirmed mechanisms include DNA-Cytosine-methylation, Cytosine-hydroxymethylation and covalent histone modifications such as histone lysine-methylation. We are particularly interested in the study of PRC2, which catalyzes the di- and tri-methylation of Histone 3 on Lysine residue 27 (H3K27me3). This modification is associated with gene repression and plays a critical role in both normal development and in cancer. Small molecule inhibitors of the catalytic component EZH2 are in development, and are likely of therapeutic benefit in tumors with overactive function of PRC2, such as some solid tumors (Breast, Prostate) and some lymphomas. Impaired function of PRC2 is found in certain cancers of the bone marrow, including early T-cell acute lymphoblastic leukemia (T-ALL), myelodysplastic syndrome (MDS), and myeloproliferative syndrome. We believe that a higher resolution understanding of the signaling changes associated with changes in Ezh2 functioning will unveil molecular vulnerabilities relevant for targeted therapies.
Our recent study using genetic models of PRC2 inactivation in MLL-AF9 AML demonstrate a role for Ezh2 in leukemic progression. Furthermore, these studies prove an absolute requirement for some level of PRC2 functioning in MLL-AF9 leukemia, as complete genetic inactivation of PRC2 by Eed-inactivation abrogates leukemic growth in vitro and in vivo. We will use this model to more fully characterize the cellular signaling mechanisms dysregulated by manipulation of PRC2. To this end, we use detailed genome-wide analysis of leukemia models by expression profiling and Chip-Seq.
We are also interested in studying the interaction of PRC2 with other epigenetic mechanisms. We collaborate closely with the Bernt-lab at UC Denver, which has a related and complementary research focus. Our overall goal is to contribute to the development of novel targeted leukemia therapies.