Neil E. Kay, M.D. Mayo Clinic

CLL-STROMA INTERACTION

CLL Microenvironment: Role of Mesenchymal Stomal Cells in Disease Progression

Grant Awarded in 2008

Abstract:

Recent evidence suggests that the microenvironment (the physical space in the bone marrow where CLL cells reside), with its complex network of physical and chemical signals, affects the proliferation rate and survival of CLL cells. We, therefore, plan to investigate several characteristics of one of the cells in the microenvironment called mesenchymal stromal cell (MSC). The MSCs will be obtained from bone marrow biopsies of CLL patients. We believe that these cells will provide crucial information to better understand the factors that are involved in disease progression in CLL.

In the first aim, we want to determine if MSCs are "true" stem cells. We will do this by studying the following characteristics: protein expression on the surface of the cell, the ability to mature into more differentiated cells and the ability to secrete chemical products. We know that MSCs from patients with CLL are able to support the CLL cells and prolong their survival. We plan to compare the ability of MSCs obtained from normal individuals to provide the same enhanced survival to CLL cells. Furthermore, we plan to compare the protective effect of MSCs from CLL patients with low-risk disease (slow or no clinical progression) with the MSCs of patients with high-risk CLL (rapid progression).

The second aim is to study the reciprocal (two-way) interaction between the CLL cells and the MSCs. We are particularly interested in knowing what specific messages are activated in MSCs of patients with low-risk CLL versus high risk disease. We will evaluate the factors involved in making the MSCs more effective in favoring CLL cell survival, activation and proliferation. Is an MSC more effective in induction of CLL B-cell survival if it has been exposed to a CLL B-cell population?

We will also evaluate the so-called "angiogenic switch" phenomenon. This is a process during which the MSC influences the CLL cells in their ability to release substances involved in new blood vessel formation. The possible subsequent increase in blood-vessel production is known to be associated to disease progression. These substances can also directly increase the CLL B-cell survival capacity.

Finally, in our third aim, we will use the information obtained in aims one and two to design a therapeutic strategy that can block the crucial point of interaction between the MSC and CLL cells, and therefore diminish the MSCs protective effect. We hope this will allow us to develop novel therapeutic strategies for our patients.