SHIP protein identified as a B-cell tumor suppressor

October 19, 2010

LA JOLLA, Calif., October 18, 2010 - Lymphoma is a cancer of the immune system. White blood cells divide again and again, spreading abnormally throughout the body. Lymphomas can arise from two types of white blood cells, T cells or B cells, which divide uncontrollably when the molecular mechanisms that keep them in check go awry. A new study led by Robert Rickert, Ph.D., professor and director of the Inflammatory Diseases Program at Sanford-Burnham Medical Research Institute (Sanford-Burnham), explores the roles of two enzymes, called SHIP and PTEN, in B cell growth and proliferation. The results, published online on October 18 in The Journal of Experimental Medicine, show that SHIP and PTEN act cooperatively to suppress B cell lymphoma. This new information could impact several anti-lymphoma therapies currently in development.

"PTEN usually gets all the attention," Dr. Rickert explained. "But here we show for the first time that SHIP is also a major tumor suppressor in B cells."

T cells destroy infected cells, while B cells produce antibodies to neutralize foreign particles. To maintain enough of these cells to mount an immune response, but not so many that lymphomas develop, PTEN and SHIP keep a damper on PI3K, an enzyme that promotes cellular growth, survival and proliferation. PI3K signaling is altered in a number of different cancers. If PTEN is missing in T cells, the damper is removed, cells grow out of control and T cell lymphomas result. Surprisingly, this study showed that B cells deficient in either PTEN or SHIP are fine. But if mouse B cells are engineered to lack both PTEN and SHIP, lethal B cell abnormalities develop.

Could PTEN and SHIP mutations actually lead to lymphoma in humans? In an earlier collaborative study with Michael David, Ph.D., at the University of California, San Diego, Dr. Rickert and colleagues showed that inflammation - such as occurs after infection or injury - reduces SHIP expression. The current study suggests that while PTEN mutation in B cells alone might not cause harm, a single mutation plus inflammation could be a double whammy that gives rise to lymphoma.

"People often talk about one gene relating to one cancer," Dr. Rickert said. "But cancer is multigenic - it takes multiple hits to subvert a cell from normal to abnormal. Here we have a model showing how that can happen in B cells."

In addition to increasing our understanding of B cell biology, this research has implications for lymphoma treatments currently in development. One such treatment targets drug-resistant B cells by depleting the body of BAFF, a compound that promotes their survival. In this new B cell lymphoma model, however, Dr. Rickert and colleagues found that B lymphoma cells still proliferate without BAFF.

On a more positive note, this study supports the development of anti-lymphoma drugs that mimic PTEN and SHIP activity by inhibiting PI3K. "Several companies are making PI3K inhibitors to treat certain kinds of lymphomas," Dr. Rickert said. "I think this system could provide a useful new preclinical model to study PI3K-dependent B cell malignancies. "
-end-
This study was funded by the National Heart, Lung and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI) at the National Institutes of Health (NIH). For more information about Sanford-Burnham research, visit http://beaker.sanfordburnham.org.

Original paper

Meletic AV, Anzelon-Mills A, Mills DM, Omori SA, Pedersen IM, Shin D-M, Ravetch JV, Bolland S, Morse III HC, Rickert R. Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. Journal of Experimental Medicine. Published online October 18, 2010.

About Sanford-Burnham Medical Research Institute

Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 - 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.

Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. Sanford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.

Sanford-Burnham Prebys Medical Discovery Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.