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Upstate student’s cancer research project makes journal cover

A research project led by Upstate Medical University graduate student Stephen Shinsky made the cover of the Oct. 23 Journal of Biological Chemistry and will pave the way for further studies of a protein linked to causing–and possibly treating–cancer.

While conducting research into the Mixed Lineage Leukemia protein-3 complex (MLL3), Shinsky “noticed this weird finding and really took charge, coming up with experiments on his own,” said his mentor Michael Cosgrove, PhD, associate professor of biochemistry and molecular biology.

“The structure of the MLL3 protein complex presents a significant technical challenge,” Cosgrove said. “It’s big, with five components. Working on one protein is hard. Working on how one interacts with another, the challenges increase exponentially.”

But Cosgrove had faith in Shinsky, who recently received his PhD and accepted a post-doctoral position at the University of North Carolina at Chapel Hill.

“He was the guy to handle it,” Cosgrove said. “It’s gratifying as a mentor when a student becomes independent and takes charge.”

What Shinsky found was that a subunit that interacts with the MLL3 protein known as WDR5 behaves differently in the MLL3 complex than it does in MLL1 and MLL2 complexes.

“We expected similar behavior, but Stephen found out otherwise,” Cosgrove said. The discovery can help researchers understand the regulation of activity in cells implicated in aggressive leukemias that affect infants and, in some cases, adults taking anti-cancer medication.

“The amount of MLL3 mutations that have been found in cancers in recent years is astounding,” Shinsky said.

“However, how these mutants affect MLL3 is not really known. Our work lays the groundwork for understanding the MLL3 core complex.”

Researchers can “easily now generate the MLL3 cancer mutants and perform studies like those in my paper and compare how cancer mutants affect the MLL3 core complex in vitro,” Shinsky said.

It took many nights and weekends in Weiskotten Hall to get to that point.

“I had to do a lot of experiments to prove that the WDR5 subunit was indeed inhibiting MLL3,” Shinsky said. “WDR5 does not appear to inhibit any of the five other highly related proteins in the same family as MLL3.”

That finding was included in an earlier paper Shinsky authored, but what he really wanted to do was craft an entire paper around it. That project, with Cosgrove’s assistance, became the JBC cover article with Shinsky as first author.

“Dr. Cosgrove was supportive in letting me direct an entire project myself and finally that came to fruition with the latest paper,” Shinsky said.

An additional element of the MLL3 research is the possibility that it can act as a tumor suppressor and prevent cancer progression.

“Our discovery that the WDR5 subunit inhibits the enzymatic activity of MLL3 may suggest that agents designed to interfere with the interaction of WDR5 and MLL3 could stimulate activity and be therapeutic,” Shinsky said. “Of course it would have to be shown that the enzymatic activity of MLL3 is required for its tumor suppressor capabilities.”

The Cosgrove lab previously developed agents that interfere with WDR5 binding to MLL3 family members. Shinsky has shown that these agents increase the enzymatic activity of MLL3, “so it may be that these agents could be used to treat cancers where MLL3 mutations reduce enzymatic activity,” he said.

Where can this work with MLL3 lead?

Perhaps to a successful result similar to the structure-based design and development of HIV protease inhibitors to treat AIDS, and tyrosine kinase inhibitors such as Gleevec that target the BCR-Abl oncogene in previously fatal chronic myelogenous leukemias, Cosgrove said.

“The key is targeted therapeutics,” he said. “That’s what this is about. Understanding the intricacies of how these proteins work at the molecular level will lead to new and better treatments.”

The Cosgrove lab will continue Shinsky’s project while he tackles cancer research at the University of North Carolina at Chapel Hill, working on different aspects of gene expression.

He has nothing but praise for Upstate and the Cosgrove lab.

“I had a lot of freedom to work independently but was able to check in with Dr. Cosgrove as often as I’d like,” Shinsky said. “Sometimes I was in his office 10-plus times a day showing him data and discussing my next experiments.

“We really worked very well together and were able to accomplish a lot in a short amount of time,” Shinsky said, referring to his relatively short four-year path to a PhD.

“I learned a lot from him and not just about science, but about how to think problems through. I will certainly miss working with him. Our ability to coordinate our different work styles into a synergistic force was really responsible for the success of this cover article and our other publications.

from With Distinction

Caption: Stephen Shinsky, center, and the Cosgrove lab at Upstate. From left, lab manager Susan Viggiano; post-doctoral associate Nilda Alicea-Velazquez; Stephen; Associate Professor Michael Cosgrove, PhD, and graduate student Kevin Namitz.

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