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Study Reveals How a Longevity Gene Protects Brain Stem Cells From Stress

A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, according to a new study by Weill Cornell Medicine investigators.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3). That discovery led Dr. Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during aging.

Jihye Paik, PhD
Associate Professor of Pathology and Laboratory Medicine

In 2018, Dr. Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells. Their new study, published Jan. 28 in Nature Communications, reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.

“Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” said Dr. Paik, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr. Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she said. This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she said.

Dr. Steven Josefowicz Awarded Starr Cancer Consortium Grant

The Starr Cancer Consortium has awarded grant funding to three Weill Cornell Medicine-led multi-institution teams to advance their groundbreaking cancer research projects. The grants will support studies on mechanisms that drive lymphoma and urothelial cancers, and the effects of radiation therapy.

Steven Josefowicz, PhD
Assistant Professor of Pathology and Laboratory Medicine

Established by the Starr Foundation in 2006, the Starr Cancer Consortium is a collaboration among five leading research institutions: The Broad Institute of MIT and Harvard, Cold Spring Harbor Laboratory, Memorial Sloan Kettering Cancer Center, The Rockefeller University and Weill Cornell Medicine.

Each year, investigators from these institutions propose new strategies to improve the prevention, diagnosis, treatment and fundamental understanding of cancer. A review board of scientists from institutions outside the consortium selects the best of these proposals for funding, with an emphasis on identifying ambitious projects that have the potential to transform the field. This year, the winners include projects led by Drs. Lewis CantleyBishoy Faltas and Steven Josefowicz of Weill Cornell Medicine.

"Weill Cornell Medicine investigators have excelled once again in receiving grant funding from The Starr Foundation's annual competition, with members of our faculty leading three of the 10 funded projects," said Dr. Hugh Hemmings, senior associate dean for research and chair of the Department of Anesthesiology. "The generous support of the foundation enables these talented investigators to pursue innovative and collaborative approaches to tackle some of the toughest problems in cancer research."

Scientists Discover a Key Genetic Driver of Lymphomas

Mutations in proteins called histone H1, which help package DNA in chromosomes, are a frequent cause of lymphomas, according to a study led by researchers at Weill Cornell Medicine, NewYork-Presbyterian and The Rockefeller University. The findings could lead to new approaches to treating these cancers.

Scientists in recent years have observed that mutations in histone H1 genes occur in lymphomas, but they have not known whether these mutations are causes or effects of malignancy. The study, which appears Dec. 9 in Nature, reveals that certain histone H1 mutations are indeed drivers of lymphoma, and promote these cancers by loosening areas of DNA that are normally tightly wrapped. This loosening allows aberrant expression of early development genes that are normally completely shut down in the mature lymphocytes from which lymphomas derive. 

Ethel Cesarman, M.D., Ph.D.
Professor of Pathology and Laboratory Medicine

“It’s a very interesting set of findings that give us insights into the origins of lymphomas as well as the important role of histone H1 proteins in the maturation of cells,” said co-senior author Dr. Ari Melnick, the Gebroe Family Professor of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

The other co-senior authors on the study were Dr. Ethel Cesarman, a professor of pathology and laboratory medicine at Weill Cornell Medicine and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center, and Dr. Alexey Soshnev, a postdoctoral associate in the laboratory of Dr. David Allis, the Joy and Jack Fishman Professor at The Rockefeller University.

Lymphomas are relatively common cancers. Each year around 85,000 people in the United States are diagnosed with them, and more than 20,000 people die of them. Most lymphomas arise from immune cells called B cells, which make antibodies.

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