Jan. A. Burger, M.D., Ph.D. University of Texas MD Anderson Cancer Center

BIOLOGY

Microenvironmental regulation of survival and growth of B lymphocytes from patients with chronic lymphocytic leukemia (CLL)

Grant awarded in 2005

Abstract:

Chronic lymphocytic leukemia (CLL) is characterized by the relentless accumulation of neoplastic B lymphocytes (CLL cells) in the blood, lymphatic tissues, and the bone marrow. Despite major advances in treatment, CLL currently is considered incurable with standard treatments and new therapeutic approaches therefore are urgently needed. In patients, CLL cells accumulate not because they grow faster, but because they survive longer than normal cells. However, when CLL cells are removed from the patient and placed into cell culture, they rapidly undergo cell death unless they are cultured in contact with "feeder" cells. Therefore, it is hypothesized that contact with "feeder" cells such as stromal cells or nurse-like cells is essential for growth and survival of CLL cells.

CLL cells are tethered to "feeder" cells in the bone marrow or the lymphatic tissues by a factor called "CXCL12" which is secreted by "feeder" cells and binds to CXCR4 receptors on CLL cells. We previously demonstrated that CXCR4 blocking molecules inhibit the contact between CLL cells and their nurturing counterparts and thereby make them more sensible to spontaneous or chemotherapy-induced cell death. However, the protective effect of "feeder" cells was only partially antagonized by CXCR4 blockers. This research proposal will further dissect which other molecules participate in supporting CLL cells in their microenvironment. Different factors that may be involved in this process will be placed alone or in combination in culture with CLL cells and we will assess whether they can substitute the "feeder" cell effect.

In parallel, studies will be performed to demonstrate the presence of these factors in tissue sections from CLL patients. Such a dissection of the interactions between CLL cells and their supportive microenvironment will allow us to identify new potential targets for improvement of current treatments for CLL patients.