Many antiapoptotic proteins are expressed in multiple myeloma (MM) cells. Among these proteins, the Bcl-2 family member Bcl-xL is frequently overexpressed in MM cell lines and MM patient cells and promotes tumor cell survival. The expression of both Bcl-xL, as well as that of the antiapoptotic Mcl-1, is regulated by signal transducer and activator of transcription 3 (STAT3), a downstream target of Janus kinases (JAKs). Specifically, Catlett-Falcone et al have reported that inhibition of STAT3 activation down-regulates Bcl-xL expression, thereby promoting MM cell apoptosis.1 To date, however, the role of genetic modulation of Bcl-xL in MM pathogenesis has not been defined.
In order to clarify the role of Bcl-xL expression in the development of normal and malignant plasma proliferation, Linden and colleagues (page ) used the κ immunoglobulin (Ig) gene 3′ enhancer to direct transgenic Bcl-xL expression to late-stage B cells in mice. The resultant phenotype included increased numbers of B-lineage cells in bone marrow and extramedullary sites, increased polyclonal serum Ig, and increases in T-cell–independent antigen-specific Ig production, consistent with a nonmalignant B-lineage proliferation. They then crossed these mice with Eμ/c-Myc transgenic mice, and the resultant phenotype included further increased numbers of B-lineage cells, including clonally related bone marrow plasma cells associated with osteolytic bone lesions. This mouse model therefore shows that the κ Ig gene 3′ enhancer can target gene expression to late-stage B cells, identifies a role for Bcl-xL in plasma cell proliferation, and demonstrates the cooperative role of Bcl-xL and c-Myc in generation of clonally related plasma cell proliferation.
This model represents an advance in our ability to examine the role of genetic abnormalities in the pathogenesis of malignant and nonmalignant B- and plasma cell proliferative disorders. Of particular note is the bone marrow plasmacytosis and associated bone disease characteristic of human MM. This model can be used to examine the role of other individual molecules in normal and malignant plasmacytogenesis, which may have implications for pathogenesis of human MM. In about half of human MMs, a primary chromosomal translocation results in the ectopic expression of an oncogene, leading directly (11q13-cyclin D1 and 6p21-cyclin D3) or indirectly (4p16-, 16q23-, and other-cyclin D2) to cyclin D dysregulation.2 In the other half of tumors there is frequent hyperdiploidy, and cyclin D1 is dysregulated by an as-yet-undefined mechanism that may involve interaction with bone marrow stromal cells. Translocations of c-Myc appear to be secondary events associated with disease progression. The antiapoptotic proteins Bcl-2 and Mcl-1 are expressed in human MM, and oncogenic Ras and tumor suppressor p53 abnormalities are present in subsets of patients. The present model may allow for delineation of the pathogenic role of these and other molecules as primary or secondary events in the pathogenesis of nonmalignant and malignant plasma cell proliferative disorders.
