Multiple myeloma is a disease characterized by the significant accumulation of malignant plasma cells in the bone marrow. There is a clear need to achieve a better understanding of the mechanisms underlying myeloma cell growth and survival control. It is important to note that the overall proliferative index of this tumor is quite low by comparison with other malignancies. Thus, an equally important clinically relevant aspect of myeloma cell biology is the mechanisms that underlie malignant plasma cell resistance to apoptosis leading to prolonged survival and tumor cell accumulation. Our current lack of knowledge concerning this process in myeloma is paralleled and amplified by our current lack of insight into signals that regulate survival of normal bone marrow resident, long-lived plasma cells. Therefore, it remains unclear whether tumor cells undergo a specific transformation-associated biological change(s) to acquire this property, or whether they exploit and amplify intrinsic tools, present in normal plasma cells, to ensure their survival.
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 member of the tumor necrosis factor family, was expressed in an autocrine1 manner by some leukemic B cells as well as by some myeloma cells. This observation is of great interest because 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. Although BAFF-R appears to be the primary receptor underlying BLyS-regulated B cell development and survival, the precise role that each receptor plays in normal B cell and malignant plasma cell biology remains unknown and is therefore the subject of ongoing work in the laboratory.
Work thus far has taken advantage of the well-characterized panel of cytokine-responsive myeloma cell lines established in our laboratory over the past 10 years. Access to primary patient tumor cells has allowed us to make a number of observations. First, we have demonstrated that all of our myeloma cell lines express BLyS mRNA as do the majority of primary myeloma cells tested to date. Moreover, we have been able to detect BLyS at the protein level. Because normal resting B lineage cells do not express BLyS, we believe this is a striking result and has direct clinical implications. Second, we have demonstrated that myeloma cells express a heterogeneous2 pattern of receptor expression for BLyS/APRIL and that one or more of these receptors are active as evidenced by the ability of exogenous3 BLyS and APRIL to augment myeloma cell growth and enhance cell survival. These observations, taking together with the striking effects of BLyS on normal B cell maintenance and survival support the overall hypothesis that the BLyS/APRIL-TACI/BCMA/BAFF-R ligand-receptor system may be involved in the pathogenesis and maintenance of multiple myeloma. In an effort to test this hypothesis, current work centers on a number of integrated projects. First, we are using a variety of methodologies to elucidate the precise impact of BLyS and APRIL on both normal and malignant plasma cell (myeloma cell) survival and growth. In accompanying studies, we are characterizing the down-stream signaling and genetic consequences of BLyS and APRIL activation in malignant plasma cells. Finally, we are very eager to better understand how myeloma cells acquire the ability to express autocrine BLyS given its ability to support myeloma cell survival.
TERMS & DEFINITIONS
Autocrine - Denoting a mode of hormone action in which it binds to receptors on and affects the function of the cell type that produced it.
Heterogeneous - Composed of parts having dissimilar characteristics or properties.
Exogenous - Derived or originating externally; produced outside of an organism, a tissue, or a cell.
Editor's Note: This research project is supported in part by an IMF donation to the Robert A. Kyle Fund for Multiple Myeloma Research. As such, this project is subject to detailed peer review.