Recent studies in my laboratory have identified a novel pathway promoting enhanced survival of chronic B cell malignancies. We demonstrated that B lymphocyte stimulator (BLyS), a newly identified tumor necrosis factor (TNF) family member, was expressed in an autocrine manner in leukemic B cells and we have preliminary data that a similar mechanism may also be operative in multiple myeloma. BLyS is critical for maintenance of normal B cell development and homeostasis and shares significant homology with a proliferation-inducing ligand (APRIL). APRIL stimulates tumor cell growth as well as proliferation of primary lymphocytes and is expressed by a variety of human cancers. Three receptors for BLyS and APRIL have been identified: B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI), and BAFF-R. Whereas BLyS binds to all three receptors, APRIL only binds to TACI and BCMA. Currently, the precise role that each receptor plays in normal or malignant B cell biology, particularly terminally differentiated plasma cells, remains unknown. We have exciting preliminary evidence that these receptors are expressed in a heterogeneous fashion in myeloma cells; that exogenous BLyS and APRIL augment myeloma cell growth and enhance cell survival; and that autocrine BLyS may be expressed by myeloma cells. Furthermore, preliminary gene profiling experiments suggest that both of these molecules stimulate the induction of a variety of genes, including a number of transcription factors previously linked to differentiation in B cells as well as other cell types. Because of the striking effects of BLyS on normal B cell maintenance and survival and our own preliminary data, the central hypothesis of this proposal is that the BLyS/APRIL-TACI/BCMA/BAFF-R ligand-receptor system may be involved in the pathogenesis and maintenance of multiple myeloma. Our central hypothesis has two separate, but highly integrated components. First, we hypothesize that myeloma cell expression of BCMA, TACI, and/or BAFF-R is critical to tumor cell survival and may reflect exploitation of a receptor-ligand system that is also critical for normal plasma cell survival. Moreover, we hypothesize that these three receptors possess both unique and redundant properties, which may be revealed by the precise pattern and/or level of receptor expression. Second, we hypothesize that activation of an autocrine BLyS pathway in myeloma cells is a novel mechanism by which this survival pathway is further exploited in malignant plasma cells. We propose three specific aims: 1) elucidate the impact of BLyS/APRIL on normal and malignant plasma cell survival and growth; 2) characterize the down-stream signaling and genetic consequences of BLyS/APRIL activation in malignant plasma cells; and 3) define the mechanism(s) underlying atypical myeloma cell expression of BLyS. Studies of this nature have the potential to suggest new opportunities to treat this disease as well as provide basic insight into the role of this novel and intriguing family of molecules in fully differentiated B lineage cells.
