'Nurse-Like' Cells Are Thethered to CLL Cells by CXC12

[Guest guest]

" Microenvironmental regulation of survival and growth of B

lymphocytes from patients with Chronic Lymphocytic Leukemia (CLL). "

Jan Burger, M.D., Ph.D.

University of Texas M.D. Cancer Center

Abstract:

Chronic lymphocytic leukemia (CLL) represents the most common type of

adult leukemia in western societies and 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 non-tumoral " 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 accessory 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.