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Maryalice Stetler-Stevenson, M.D., Ph.D.

Laboratory of Pathology Staff Clinician Building 10 Room 2N108 Bethesda, MD 20892 Phone:   301-402-1424 Fax:   301-402-0536 E-Mail:   stetler@mail.nih.gov

Biography

Dr. Stetler-Stevenson received her Ph.D. and M.D. from Northwestern University Medical School, Chicago, where she also trained in anatomic pathology. She completed a fellowship in hematopathology in the Laboratory of Pathology, NCI, before becoming Chief of the Flow Cytometry Unit. Dr. Stetler-Stevenson's interests include the study of factors active in lymphomagenesis and progression in lymphoid neoplasia as well as advancing the state of the art in the field of clinical flow cytometry.

Research

Lymphomagenesis and Progression of Hematopoietic Neoplasms

The Flow Cytometry Unit provides and develops specialized diagnostic procedures utilizing cytometric techniques as a clinical service. The Unit also conducts translational research into mechanisms of lymphomagenesis. Homeostasis in lymphoid tissues is maintained by close regulation of lymphoid cell proliferation and programmed cell death, or apoptosis. Inhibition of apoptosis can result in a neoplastic expansion of lymphoid cells (i.e., lymphoma) due to unchecked proliferation. In addition, genetic events leading to inhibition of programmed cell death result in resistance to numerous chemotherapeutic regimens as well as gamma-radiation. Factors that inhibit apoptosis can therefore result in formation of lymphomas with poor prognosis due to resistance to treatment. The Flow Cytometry Unit is studying the contribution of tissue inhibitors of metalloproteinases (TIMPs) to lymphoid homeostasis and lymphomagenesis.

The tissue inhibitors of metalloproteinases (TIMPs) are a family of closely related proteins that were initially described as inhibitors of the matrix metalloproteinases. In addition to blocking matrix metalloproteinase activity, TIMPs also have growth factor-like activity. We have found that TIMP-1 is expressed by neoplastic B cells and this expression is associated with a more aggressive phenotype. TIMP-1 expression in B cells correlates with the germinal center phenotype that occurs with the generation of lymphoblasts, and TIMP-1-expressing lines can be described as mature, activated B cells in a preplasma cell stage. Induction of TIMP-1 expression induces further differentiation in B cells in that it upregulates the activation marker CD23 as well as the survival antigen CD40, downregulates CD77 as well as surface immunoglobulin expression and induces expression and secretion of IL-10. CD77 expression is highly restricted to germinal-center B lymphocytes and is a neutral glycolipid expressed by a subset of B lymphocytes that readily enter programmed cell death. Apoptosis in these cells is prevented by CD40 engagement and by soluble CD23. Rescue from apoptosis by CD40 is mediated by a Bcl-2-independent mechanism. Based upon these previous studies, a model of B cell maturation has been proposed in which ligation of CD40 drives cells to loose CD77 and express membrane and soluble CD23, which in turns acts as an autocrine factor. Thus, TIMP-1 may play a role in the normal development of the B cells in that it may provide an extracellular membrane signal to prevent programmed cell death. Further studies revealed that TIMP-1 promotes cancer cell growth through inhibition of programmed cell death. TIMP-1 expression in Burkitt's lymphoma cell lines confers resistance to Fas, radiation, cold shock, and serum starvation-induced apoptosis. TIMP-1's inhibition of both Fas-dependent and Bcl-2-dependent pathways is highly unusual and indicates a potential for far-reaching effects on cell growth and homeostasis. This antiapoptotic effect is novel, appears receptor mediated, and is not due to inhibition of matrix metalloproteinase activity. Since Bcl-2 has been shown to inhibit apoptosis in B cells, we determined whether Bcl-2 or the related proteins are implicated in the TIMP-1 protective effect. Although upregulation of TIMP-1 does not enhance expression of Bcl-2 or the Bcl-2 homolog Mcl-1, it clearly upregulates Bcl-X_L.

In addition to controlling several genes in B lymphocytes, including the immunoglobulin light-chain gene, the transcription factor NFkappaB has been reported to induce expression of antiapoptotic genes in B cells. We therefore studied expression of NFkappaB p65 (Rel A) and found no change in the cytoplasmic expression of NFkappaB with induction of TIMP-1 expression. However, higher expression of the NFkappaB inhibitor IkappaBalpha is observed, indicating a decrease in NFkappaB activity. Consequently, NFkappaB activation does not appear to be involved in the induction of antiapoptotic proteins by TIMP-1. Interestingly, this decreased NFkappaB activity is also supported by our results showing downregulation of immunoglobulin expression by TIMP-1. Furthermore, TIMP-1 suppression of PCD did not correlate with levels of cell surface CD95 expression. These results suggest that TIMP-1's antiapoptotic mechanism is not mediated by Bcl-2 or suppression of CD95 expression, but likely by inducing Bcl-X_L. Also, upregulation of Bcl-X_L by TIMP-1 appears to be independent of NFkappaB activation.

In summary, TIMP-1 expression in B cells inhibits programmed cell death by a novel mechanism and may be a negative prognostic factor in B cell non-Hodgkin's lymphoma. TIMP-1 inhibition of apoptosis may disrupt lymphoid homeostasis, resulting in development of lymphoma through uncontrolled neoplastic proliferation of lymphoid cells as well as resistance by the neoplastic cells to conventional cancer therapies. The laboratory is currently studying the role that TIMP-1 may play in B cell differentiation and function.

This page was last updated on 7/15/2008.