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Olivier Elemento Thousands of mysterious genes underlie the most common form of non-Hodgkin lymphoma, researchers at Weill Cornell Medicine have found in a new study. Their discovery illuminates a new layer of gene regulation that may drive cancer, and may lead to more effective targets for treating it.

Diffuse large B-cell lymphoma is an aggressive blood cancer that accounts for as much as 30 percent of all non-Hodgkin lymphoma cases diagnosed each year in the United States. Scientists have long studied the molecular underpinnings of the disease in the hope of better understanding how it develops.

Now, Weill Cornell Medicine investigators say that they've discovered thousands of new genes in 116 human samples of lymphoma. These genes produce long non-coding RNAs, known as lncRNAs. Unlike RNA that produces proteins that enable the body to do its work, the lncRNA appear to switch on — or off — other genes that make proteins, researchers say. They counted 2,632 different forms of these unusual RNA molecules. They also found a substantial number of the same or similar lncRNAs in canine lymphoma. The findings, published Nov. 2 in Genome Medicine, may shed new light on both the nature of lncRNAs — discovered only a few years ago — and how they could promote DLBCL and perhaps other cancers.

"While we don't know precisely what these molecules are doing, the fact that the majority — about two-thirds — of the long non-coding RNAs we found are expressed exclusively in lymphoma, and that many are found in both human and dog lymphoma, tells us that they are likely playing fundamental roles in this cancer," said senior author Dr. Olivier Elemento, an associate professor of computational genomics in the Department of Physiology and Biophysics who heads the Laboratory of Cancer Systems Biology in the Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine at Weill Cornell and co-chairs the Meyer Cancer Center Program in Genetics, Epigenetics and Systems Biology.

"It is fascinating to us that after so many years spent decoding the genome, you can still find another 2,000-plus genes that look like regular genes — have all the features of normal genes — but which don't code for proteins," he added.

The researchers gained insights into the function of these lncRNAs when they found that expression of certain normal genes and the non-coding genes occurred at the same time, suggesting that lncRNAs were either activating or inactivating genes that produced protein. They were then able to connect lncRNA expression to genes whose protein function is known, and found that a network of lncRNAs seemed to be working together to regulate genes globally.

"We think these lncRNAs are networked in some way — to each other and to protein-coding genes — and are regulating protein production," Dr. Elemento said. "That's pretty amazing considering these two kind of genes come from different places in the genome."

If lncRNAs are found to be regulating aspects of the development and growth of this lymphoma, it may be possible to design drugs that turn off their function, he added. Such drugs, known as antisense oligonucleotide pharmacology, basically act like Velcro, zipping up the single strands of lncRNAs with a complementary strand and inactivating them, he said.

"Bound like that, IncRNAs would be unable to function."