Ari Melnick, MD, a professor of medicine at the Weill Cornell Medical College, discusses EZH2 and its potential as a target in diffuse large B-cell lymphoma (DLBCL).

Melnick says the epigenetic modifier protein EZH2 is an emerging target in DLBCL that has shown promise. This protein is highly expressed in DLBCL as well as in prostate and breast cancer tumors. Studies have shown that EZH2 suppresses checkpoints that stop cells from dividing. If EZH2 is inhibited in lymphoma cells, Melnick says, they will not be able to proliferate.

Other studies have shown that 30% of GCB-type DLBCL tumors and follicular lymphomas have a mutation in EZH2, which supercharges the protein to make it much stronger, Melnick says. The mutation adds three methyl groups to the tails of histone H3 lysine 27, which causes the repression of proliferation checkpoint regulatory genes and genes involved in the differentiation of B cells. Melnick says this supercharged EZH2 blocks the ability of germinal center B cells to differentiate, causing the cells to continue to divide.

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Ari Melnick, MD, a professor of medicine at the Weill Cornell Medical College, discusses EZH2 and its potential as a target in diffuse large B-cell lymphoma.

Dr. Melnick on Targeting EZH2 in DLBCL

Ari Melnick, MD, professor of medicine, Weill Cornell Medical College, discusses the association between epigenetic diversity and clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL).

It is known that tumors in individual patients are composed of many different cell clones and mutations. Researchers are also aware that tumors with more combinations of mutations in different clones of cells will have a greater chance of survival after treatment.

Melnick says that a great degree of diversity of clonal populations from an epigenetic standpoint is now being observed as well. Two studies have proven that those patients with the highest degree of epigenetic diversity are those that do the poorest, proving that epigenetic diversity is an indication or how fit tumors are to survive toxic treatment.

Dr. Melnick on Epigenetic Diversity in DLBCL

Ari M. Melnick, MD, Professor of Medicine, Weill Cornell Medical College, discusses his presentation on the epigenetic basis of B-cell lymphomas at the 17th International Congress on Hematologic Malignancies.

Melnick says that epigenetic gene regulation functions as the software that guides cells towards behavior and that this 'software' is crucial for survival and growth.

Lymphoma cells are no different than other cell types in that they require epigenetic modifications and certain patterns (or epigenetic landscapes) to exhibit the classical phenotype of lymphoma subtypes. These epigenetic marks include cytosine methylation, histone modifications, and other components of the epigenome.

Dr. Melnick on the Epigenetic Basis of B-Cell Lymphomas

Ari M. Melnick, MD, Professor of Medicine, Weill Cornell Medical College, comments on biomarkers in lymphoma.

Studies of epigenetic regulation in lymphomas are identifying clinically-useful biomarkers and revealing biological insights into how lymphomas function. Lymphomas exhibit a great degree of epigenetic heterogeneity, which is an indicator of disease aggressiveness and increases the populations of cells that can survive chemotherapy and repopulate the disease.

Cytosine methylation patterns in lymphoma are reversible. The potential remains to inhibit DNA methyltransferases and overcome the negative effects of epigenetic heterogeneity.

Dr. Ari M. Melnick on Biomarkers in Lymphoma

Ari M. Melnick, MD, Professor of Medicine, Weill Cornell Medical College, discusses the future of chemotherapy in patients with lymphomas.

Melnick believes that chemotherapy is not required to cure lymphomas. Similar to other tumor types, lymphomas are dependent on several biological factors to survive and grow.

Lymphomas depend on lineage factors: proteins that are present without which the disease cannot survive. Further, somatic mutations occur in lymphomas and are targetable or represent targetable pathways. It is possible, Melnick says, to eradicate all lymphoma cells with targeted agents or various combinations of targeted agents. It is also becoming increasingly possible for agents to erase "instructions" (epigenetic settings) to destroy the disease.

Targeting pathways, lineage factors, and epigenetic settings provide physicians with three ways to combat lymphomas.

Dr. Melnick on the Future of Chemotherapy in Lymphomas

Ari M. Melnick, MD, a professor of medicine at the Weill Cornell Medical College, explains recent interest in the protein MALT1 as a potential therapeutic targeted for patients with activated B cell—like diffuse large B-cell lymphoma (ABC–DLBCL).

MALT1 is the only known paracaspase protein in humans and is related to caspases, which play an essential role in apoptosis. Melnick believes that agents designed to target MALT1 are less likely to interact with other proteins, since no other paracaspases exist in humans.

The uniqueness of MALT1 makes it potentially more useful, Melnick believes. Additionally, MALT1 is an active component of the CBM complex, which is downstream from two active pathways that are implicated in ABC-DLBCL pathogenesis. As such, inhibiting this protein may be an effective treatment by dampening tumor signaling, Melnick proposes.

Ari M. Melnick, MD, Professor of Medicine, Weill Cornell Medical College, discusses MALT1 as a potential target for patients with activated B cell-like diffuse large B-cell lymphoma.

Ari M. Melnick, MD

Articles

Dr. Melnick on Targeting EZH2 in DLBCL

Dr. Melnick on Epigenetic Diversity in DLBCL

Dr. Melnick on the Epigenetic Basis of B-Cell Lymphomas

Dr. Ari M. Melnick on Biomarkers in Lymphoma

Dr. Melnick on the Future of Chemotherapy in Lymphomas

Dr. Ari Melnick on MALT1 as a Potential Target in DLBCL