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)

Update:

Malignant leukemia cells from patients with CLL rapidly die once they are removed from the patient's blood, bone marrow, or lymph nodes. This suggests that interactions between CLL cells and neighbor cells, called stromal cells and "nurse-like cells", that are part of the "microenvironment" in which leukemia cells live in the patients' tissues, are critical for maintenance of the leukemia cells.

The aim of the research supported by the CLL Global Research Foundation was to study which cells and molecules are important for interactions between CLL cells and their microenvironment. Initial results were submitted for publication, and also summarized in a review article published in the British Journal of Haematology.

During this funding period, we found that a molecule on CLL cells called "CXCR5" is over expressed in CLL and mediates contact between CLL cells and "nurse-like cells". Because of the high-level expression of CXCR5, and its function in migration and adhesion to "nurse-like cells," CXCR5 is an attractive therapeutic target in this disease. These results have been submitted for publication.

In order to systematically dissect the interactions between CLL cells and the microenvironment, we performed experiments to analyze which genes in CLL cells are turned on, and which genes are turned off when CLL cells are grown with stroma or "nurse-like cells". The experiments, in collaboration with Dr. Andreas Rosenwald from the Department of Pathology at Würzburg University, Germany, revealed strong up-regulation of 2 molecules that normally regulate interactions of immune cells (B-cells and T-cells). These studies are currently ongoing and are a central part of the project funded by the CLL Global.

To further evaluate if the findings in cell cultures can be reproduced with tissues from CLL patients, biopsy specimen from CLL patients were stained in collaboration with Professor A. Schmitt-Gräff (Hematopathology, Freiburg University). We found that "nurse-like cells" secrete a protein called CXCL13 that binds to CXCR5.

Collectively, the CLL Global funding allowed us to initiate studies with international collaborators to determine how CLL cells interact with the microenvironment. These studies provide novel insight into the mechanism of this disease and help to identify new therapeutic targets for CLL patients.