Mouse Model Advances Drug Development for Treating Lymphoma and Melanoma

Cancer researchers have established a mouse model system to study the involvement of EZH2 histone methyltransferase (EZH2) mutations in the development of lymphoma and melanoma tumors.

Mutated or over-expressed EZH2 has been linked to about 20% of B-cell lymphomas, 5% of melanomas, and a lower frequency of a variety of other cancers. EZH2 inhibits genes responsible for suppressing tumor development, and blocking EZH2 activity may slow tumor growth. This gene encodes a member of the Polycomb-group (PcG) family. Polycomb-group proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations.

Investigators at the University of North Carolina (Chapel Hill, USA) described a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2Y646F in humans; Ezh2Y641F in mice) was conditionally expressed. Expression of Ezh2Y641F in mouse B-cells or melanocytes caused the development of highly aggressive lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression.

Overall, results published in the May 2, 2016, online edition of the journal Nature Medicine suggested that Ezh2Y641F induced lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.

“We have shown that the biology of tumors driven by this mutation are distinct from other types of lymphoma and melanoma, and that these tumors require persistent malfunction of EZH2 for growth,” said senior author Dr. Norman Sharpless, professor of cancer research at the University of North Carolina. “While there has been significant progress in recent years against cancers such as lymphoma and melanoma, many patients still fail these newer therapies and need further options for therapy. Given that EZH2 malfunction is a common event in many types of cancer beyond lymphoma and melanoma, we are hopeful that well-tolerated inhibitors of this enzyme will benefit a large group of patients with cancer.”

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