Targeting deregulated epigenetic mechanisms in B-cell lymphomas
Professor Ricky Johnstone, University of Melbourne (Melbourne).
Funding period: 2019 – 2022.
Dr Johnstone aims to advance novel precision medicine therapies for diffuse large B-cell lymphoma (DLBCL), which accounts for one-third of patients newly diagnosed with non-Hodgkin lymphoma and is the most common form of non-Hodgkin lymphoma.
Conventional chemo-immunotherapy still has poor outcome with 40% of patients not responding to the treatment or relapsing. Therefore, there is urgent need for better understanding the biology of DLBCL in order to define new clinical biomarkers, design personalized therapies and improve clinical outcome for patients with relapsed or refractory lymphomas.
DLBCL are characterized by profound alterations in the epigenome, i.e. group of chemical modifications in the DNA and histones that regulate gene expression independently of the DNA sequence. Notably, aberrant epigenetic changes in DLBCL are correlated with poor prognosis and outcome. One of these epigenetic modifications is the addition of a methyl group to the cytosines in the DNA molecule, generally called DNA methylation. Recent clinical trials in DLBCL with drugs targeting DNA methylation suggest that pre-treatment with this epigenetic therapy could sensitize the tumor cells to subsequent chemotherapy.
This research will test therapies that inhibit a gene called TET2 that is often mutated in blood cancers, including DLBCL. TET2 is a protein involved in DNA demethylation that is mutated in around 10-15% DLBCLs, suggesting that epigenetic therapies could be beneficial for the subset of DLBCL patients withTET2 mutations. We envision that the results of this collaborative project composed of basic and translational research groups will translate into new precision medicine therapies for DLBCL patients.