Differential Response to IL-4 Offers Clues to Therapy of Diffuse Lymphoma Subtypes

Abstract

Izidore Lossos, M.D., a hematologist oncologist at the University of Miami Sylvester Comprehensive Cancer Center, is the lead author of an important lymphoma study published online by the hematology journal Blood.

Lossos and his colleagues at UM/Sylvester examined two subtypes of diffuse large-B-cell lymphoma. Patients with GCB-like large-B-cell lymphoma respond much better to chemotherapy and have much better survival rates than those with ABC-like large-B-cell lymphoma. It's difficult to distinguish between the two subtypes in pathology–but they have distinct gene expression profiles.

"We observed a totally different cascade of events in the cells from tumors with good outcome than in the cells from tumors with bad outcome in response to interleukin-4 (IL-4), a protein used for intercellular communication," said Lossos, an Associate Professor of clinical medicine at the Miller School of Medicine at UM and a member of the Leukemia, Lymphoma, and Myeloma site disease group at UM/Sylvester. "This IL-4 response may form a good target for therapy because once you reverse the cascade you can change the response to chemotherapy."

Diffuse large-B-cell lymphoma is the most common lymphoma, accounting for between 30 and 40 percent of all lymphoma cases, according to the American Cancer Society. About 25,000 Americans are diagnosed each year and fewer than half of them are cured. Large-B-cell is known as a high-grade lymphoma, which grows and spreads quickly but which usually responds to chemotherapy. This research not only helps physicians identify in advance who will respond to chemo, it tells them why - a new discovery which may open the door to new treatments.

"As far as therapeutic options, that's a work in progress," said Lossos. "We've identified a new potential target. Now we need to find how to apply it in the clinic and what therapeutic approach to use. The hope is we will be able to find a substance that will alter this response and convert the ABC-type lymphoma from a non-responder to a responder."

While IL-4 is present in many tissues, including both types of large-B-cell lymphoma, it doesn't affect both cancers in the same way. In the GCB-like, or "good" cells, IL-4 targets the cancer, activating a signaling process that tells the cells to divide rapidly. Since chemotherapy attacks and kills cells that divide rapidly, it can kill the fast-growing GCB-type, which accelerates growth in response to IL-4. In ABC-type "bad" cells, IL-4 triggers a different response, activating a pathway that slows down cell proliferation, which actually protects the malignant cells from chemotherapy.

GCB stands for germinal center B-cell. Germinal centers are regions in the body in which an active immune response develops. B-cells have an important role in immune-system. ABC stands for activated B-cell or B cells that are activated by specific stimuli in the body. To analyze expression of the genes in these lymphoma subtypes, the investigators used two methods - real¬-time polymerase chain reaction analysis (RT-PCR) and gene expression arrays, which identify and quantify gene expression.

In addition to Dr. Lossos, post-doctoral fellows Xiaoqing Lu, M.D., Hovav Nechustan, M.D. Ph.D. and UM/Sylvester physician-scientist Rakesh Singal, M.D. contributed to the study. The publication is now available online as an early release at the journal Blood, and will appear in print in the journal in the coming months. http://www.bloodjournal.org/cgi/content/abstract/2004-10-3820v1

UM/Sylvester was founded in 1992 to provide comprehensive cancer services and today serves as the hub for cancer-related research, diagnosis, and treatment at the University of Miami School of Medicine. UM/Sylvester handles more than 1,100 inpatient admissions annually, performs 2,800 surgical procedures, and treats 2,900 new cancer patients. All UM/Sylvester physicians are on the faculty of the University of Miami School of Medicine, South Florida's only academic medical center. In addition, UM/Sylvester physicians and scientists are engaged in more than 150 clinical trials and receive more than $30 million annually in research grants. UM/Sylvester at Deerfield Beach recently opened to better meet the needs of residents of Broward and Palm Beach Counties. This 10,000 square-foot facility at I-95 and S.W. 10th Street offers appointments with physicians from six cancer specialties, complementary therapies from the Courtelis Center, and education and outreach events. http://www.sylvester.org.