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January 11, 2001

Penn Researchers Answer "One Small Question," and Advance The Quest to Cure a Deadly Form of Cancer

Scientists Unlock a mystery related to Acute Undifferentiated Leukemia

Scientists studying gene regulation by a common protein compound have uncovered its link to a fatal form of leukemia, in a breakthrough that opens new lines of inquiry for researchers devoted to finding a cure for the disease.

"This is how science works at its best. You begin with an interest in how cells work, and it leads to an understanding of the relationship of basic cellular proteins to a disease," said Debabrata Chakravarti, PhD., Assistant Professor of Pharmacology at the University of Pennsylvania School of Medicine and leader of the research team that made the discovery.

The findings are published today in the journal Cell.

Chakravarti's research, which began with his interest in a specific aspect of cell transcription - the change in a cell brought about by the action of DNA and protein -- has uncovered what he describes as "a plausible mechanism" for the function of a cancer-causing gene found in aberrant bone marrow cells.

Bone marrow contains pluripotent stem cells, which can give rise to lymphocytes and myeloid cells. Myeloid cells contribute to the work of the body's immune system -- but when they fail to differentiate, and therefore cannot perform their natural function, they trigger acute undifferentiated leukemia.

At the time of Chakravati's discovery, he and his group were working to identify the function of a group of cellular proteins, known collectively as INHAT, that regulates gene activity. The protein complex functions by modifying DNA through histones - the chain of proteins that coil around DNA.

As they moved forward in defining the aspects of INHAT that have to do with cell transcription, Penn's researchers discovered the identity of one of the proteins in the INHAT sequence is SET -- a putative oncogene.

"SET is present in every cell, but it functions only as an oncogene in patients suffering from acute undifferentiated leukemia. Nobody knows why this is so -but we do know that in leukemia patients it is always found fused to a second protein called CAN," Chakravarti said. The function of the SET-CAN fusion is also a mystery.

As they unraveled the INHAT protein sequence, the Penn scientists were also able to identify the function of SET. They now understand that in normal conditions, SET "masks" histones by wrapping itself around the ends of the protein chains, helping to prevent random commands from using the histones on the DNA to activate genes inappropriately - and therefore protecting the integrity of every cell's function.

Now that SET's presence in healthy cells is understood, it will be easier for scientists to decipher what the protein's presence means when it appears as part of SET-CAN in cancer cells, Chakravarti said.

"Previously, neither the function of SET nor CAN was understood. Now that we understand at least one function, we can investigate whether the SET-CAN fusion contributes to leukemia by promoting aberrant histone modification," he said. "We can also investigate the separate function of CAN. And we can investigate how these two proteins alter one another."

"Our work answered one small question. But more important, it opens up so many new avenues of research," he said.

The study was funded by grants from the National Institutes of Health, the University of Pennsylvania Cancer Center and the University of Pennsylvania Diabetes Center.

Members of Chakravarti's staff who assisted in the research include Sang-beom Seo, PhD; Peter McNamara, PhD; Soyoung Heo, and April Turner. The study was conducted in collaboration with William S. Lane, PhD., of the Department of Microchemistry and the Proteomics Analysis Facility at Harvard University.




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