The Molecular Basis of Multiple Myeloma
The NSD2/MMSET (Multiple Myeloma Set Domain) gene was identified in the t(4;14) translocation, present in 15-20% of multiple myeloma. MMSET has proprieties of a transcriptional co-factor, including the ability to bind to sequence specific transcription factors, transcriptional co-factors and histone deacetylases. More recently we described activating point mutations of this enzyme in a number of acute lymphocytic leukemia cell lines. More recent work form the Children’s Oncology group shows that 10-20% of all children with relapsed B-cell ALL have this mutation.
Using animal models and CRISPR-mediated gene editing we are studying the mechanisms of oncogenesis and therapy resistance mediated by the mutant enzyme. We are currently screening for agents that inhibit the histone methyltransferase activity of the MMSET protein that might represent novel therapeutic agents for this form of myeloma. We are further expanding our research into other histone methyltransferease and histone demethylases recurrently mutated in multiple myeloma, one of the topics the subject of our recently funded MMRF epigenetics program grant.
The Molecular Biology of Leukemia and Lymphoma
Our lab studied a variant form of acute promyelocytic leukemia, which is highly resistant to therapy. In this syndrome the retinoic acid receptor is linked to a protein known as PLZF, which in turn is a DNA-binding repressor of gene expression. PLZF is expressed in early hematopoietic cells and is a tumor suppressor. We found that the protein contains a conserved self-association and repression domain called the BTB/POZ domain. Working with colleagues we devised a peptide that inhibits the action of the BTB domain of the closely related BCL6 factor and are working towards therapeutic trials of this agent.
We have also studied how gene expression changes in patients treated with therapies targeted to gene expression including combinations of DNA demethylating agents and histone deacetylase inhibitors. Most recently we have worked on the mutant, activated forms of EZH2 found in large cell lymphoma. We have shown hat this gain of function mutation increases global levels of histone 3 lysine 27 methylation in B-cells and represses genes involved in growth control. This work was the cover article of the May 13, 2013 issue of Cancer Cell. As a result of this work a phase I trial of EZH2 inhibitors for lymphoma is underway. Currently with collaborator Wilson Miller at McGill University we are studying mechanisms of resistance to EZH2 inhibitors.