Like their normal bone marrow plasma cell counterpart, MGUS and MM tumors are dependent on mutual interactions with cells and extracellular components of the bone marrow for survival and growth. Exceptions to this include primary plasma cell leukemia (PCL) and terminal phases of MM, which sometimes extends to extramedullary sites. Significantly, virtually all HMCL are derived from PCL or extramedullary tumor. Although not yet well understood, there is increasing evidence that some of the earliest onco-genic events differentially affect the interaction of tumor cells with bone marrow components. First, tumors in the 11+6 and D1 groups are more strongly associated with lytic bone lesions than tumors in the 4p and Maf groups (P. L. Berg-sagel, unpublished results). Secondly, the Maf transcription factor-stimulated expression of 07 integrin and other surface receptors or cytokines seems likely to influence the interactions of the Maf tumor group in the bone marrow. Thirdly, in contrast to tumors in the other TC groups, D1 tumors [hy-perdiploid with multiple trisomies and cyclin D1 expression without a t(11;14)] are greatly under-represented or absent in primary PCL and HMCL. Thus, D1 tumors may be uniquely dependent on the bone marrow environment, with the possibility that the ectopic/increased expression of cyclin D1 is dependent on the bone marrow microenvironment. For example, IL-6 secreted by bone marrow stromal cells (BMSCs) triggers phosphorylation of Akt, and downstream glycogen synthasekinase 3 (GSK-3a) in turn induces phosphorylation of cyclin D1 followed by degradation through the ubiquitin-proteasome pathway, thereby promoting the transition from G1 to S phase. Tumor necrosis factor a (TNF-a) in the bone marrow milieu activates NFkB, thereby modulating expression of adhesion molecules on both MM cells and BMSCs, and inducing IL-6 transcription and secretion in BMSCs. Ac tivated NFkB also binds to the promoter of cyclin D1, thereby regulating its expression.
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