image: This is Dr. Robert Rickert of Sanford-Burnham Medical Research Institute. view more
Credit: Nadia Borowski Scott
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. "
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.
Journal
Journal of Experimental Medicine