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Targeting deregulated epigenetic mechanisms in B-cell lymphomas

Ricky Johnstone

Ricky Johnstone

PhD

The University of Melbourne

Project Term: July 1, 2019 - June 30, 2022

Diffuse large B-cell lymphomas (DLBCL) are aggressive tumors characterized by profound epigenetic alterations. In this proposal, we seek to investigate novel epigenetic therapies to treat this type of lymphomas. Specifically, we propose to explore the use of histone deacetylases inhibitors, alone or in combination with hypomethylating agents, as a precision medicine approach to treat lymphomas that present mutations in TET2, a protein involved in DNA demethylation that is highly mutated in DLBCL

Lay Abstract

Lymphomas are a type of cancer derived from blood cells. Diffuse large B-cell lymphomas (DLBCL) account for one-third of patients newly diagnosed with non-Hodgkin lymphoma. Importantly, 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. Since this is a dynamic process, we hypothesize that epigenetic therapies aimed to reverse aberrant DNA methylation could be beneficial for DLBCL patients. In this regard, hypomethylating agents are currently used for the treatment of other type of hematological malignancies, such as myeloproliferative syndromes, and 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. We focused on ten-eleven translocation 2 (TET2), a protein involved in DNA demethylation that is mutated in around 10-15% DLBCLs. We have recently demonstrated that TET2 is a tumor suppressor in this type of lymphoma. Absence of TET2 results in aberrant DNA methylation and changes in gene expression in mature B-cells and TET2-deficient lymphoma cells become sensitive to inhibition of the histone modifier HDAC3, suggesting that epigenetic therapies could be beneficial for the subset of DLBCL patients withTET2 mutations. In this proposal, we are planning to combine mouse models, patient samples and human cell lines to 1) explore the therapeutic potential of HDAC3 inhibitors and hypomethylating agents, alone or in combination, to treat DLBCL that present TET2 mutations and 2) characterize in detail the mechanisms by which TET2 loss of function affects DNA methylation and gene expression in normal and malignant B-cells. 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.

Program
Translational Research Program
Grant Subprogram
Snowdome
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