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EZH2, BCL6 together induce germinal center-derived lymphomas
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NEW ORLEANS — The histone methyltransferase EZH2 and the transcriptional repressor complex BCL6-BCOR cooperate to induce the formation of germinal center derived lymphomas, according to research presented during the ASH Annual Meeting and Exposition.
“The combination of EZH2 and BCL6 inhibitors are highly synergistic in destroying diffuse large B-cell lymphomas and thus represent an exciting new rationally designed treatment regimen for this disease and should be tested in clinical trials,” Wendy Béguelin, PhD, research associate in the department of medicine/hematology-oncology at Weill Cornell Medical College, told HemOnc Today. “The data outline the mechanism of action of the EZH2 protein, which functions as a histone methyltransferase that silences gene expression.”
Wendy Béguelin
While EZH2 is known to be a crucial regulatory factor for stem cells, it was also identified within the immune system. Specifically, EZH2 is highly produced when B-type lymphocytes are activated to produce antibodies against invading microbes — the same cells that increase the risk for nearly all B-cell lymphomas.
Beguelin and colleagues extracted bone marrow from BCL6 knockin mice and transduced with retrovirus-encoding mutant EZH2Y641F or GFP alone and transplanted them into lethally irradiated recipients.
Only EZH2Y641F/BCL6 mice had an accelerated lethal phenotype, with reduced median survival. Serial bone marrow transplantation resulted in further increased lethality.
Given the oncogenic cooperation between BCL6 and EZH2, they hypothesized that rational combinatorial therapy with BCL6 and EZH2 inhibitors might synergistically destroy DLBCLs.
“Indeed, by combining the EZH2 inhibitor GSK343 and the RI-BPI, a drug that inhibits BCL6 by abrogating its interaction with BCoR, we observed a potent synergistic effect on the inhibition of DLBCL cell lines proliferation,” the researchers wrote. “The combination of these two inhibitors in mice bearing DLBCL xenografts accordingly suppressed tumor growth more effectively than either agent alone.”
Further, the combination yielded additional killing of primary human DLBCL cells growth in a co-culture system that researchers developed for testing primary human specimens.
For more information:
Beguelin W. Abstract #1. Presented at: ASH Annual Meeting and Exhibition; Dec. 7-10, 2013; New Orleans.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Joseph M. Connors, MD, FRCPC
This scientific paper provides important new insight into the fundamental biology of non-Hodgkin’s lymphomas, neatly knitting together two major themes that have emerged in the past decade as dominant in lymphoma evolution: enzymatically mediated histone modification and transcriptional repression, both of which lead to inappropriate germinal center proliferation and lymphomagenesis.
Prior work had demonstrated that gain-of-function mutation of EZH2Y641N leads to germinal center hyperplasia and lymphomagenesis via enhanced trimethylation of histone 3 lysine 27 (H3K27), and that constitutive overexpression of BCL6 — typically induced by balanced translocation involving chromosome 3 — leads to B-cell hyperproliferation.
Beguelin and colleagues now neatly demonstrate that enzymatic complexes of mutated EZH2 and overexpressed BCL6 cooperate to induce lymphomas in mice and that specific inhibitors of both mutated EZH2Y641N and normal BCL6 synergistically kill lymphoma cells and tumor xenografts caused by these cooperating enzymatic complexes. Thus, they not only explicate the induction of malignant lymphomas but also identify effective targeted therapeutic intervention. Findings such as these prove that intensive exploration of lymphoma biology leads directly to new approaches to therapy. This type of scientific work is most interesting because it moves us away from empiric trial-and-error–based treatment discovery directly into biology-based targeted therapy. Approaches such as this deliver on the promise that deeper biologic understanding translates directly into more effective, rational therapeutic intervention.
The next step is to translate these observations, which were derived in mice, into the clinic. The biology is elegant and the effects clear cut. Now we need to find out if they will really work in actual patients. This is high-impact work. Laboratory scientists should see these discoveries as validation that exploring basic biology pays off. Clinicians should be encouraged that deep science can produce rationally based effective new treatments. Finally, this type of collaborative work shows that scientists and clinicians from around the world (New York, Pennsylvania, Chicago and Vancouver) can cooperate effectively, amplifying what they each can contribute.
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