New insights into role of microenvironment in multiple myeloma. B New insights into role of microenvironment in multiple myeloma. B. A model integrating the temporal variation in DKK1 expression in the natural history of a subtype of myeloma that interacts closely with cells of the bone microenvironment. During the earliest stages of myeloma (disease progression is depicted from left to right) myeloma plasma cells (cells with blue nucleus and purple cytoplasm) grow in a diffuse-interstitial pattern and do not exhibit MRI- or radiography-defined bone lesions. Myeloma plasma cells at this stage do not express DKK1. Mesenchymal stem cells also termed marrow stromal cells (MSCs), characterized as STRO-1-positive, IL-6-positive, receptor activator of NF-κB ligand (RANKL)-positive, and alkaline phosphatase (ALP)-negative, express the Wnt receptors FZD and LRP5 and respond to Wnt signal by stabilizing cytoplasmic β-catenin, which, in turn, translocates to the nucleus where it interacts with latent TCF/LEF transcription factors to induce target genes resulting in differentiation of MSCs into mature bone-mineralizing osteoblasts, characterized as ALP-positive, osteoprotegerin (OPG)-positive, STRO-1-negative, RANKL-negative, and IL-6-negative. During disease progression, myeloma plasma cells begin synthesizing DKK1. The mechanism by which DKK1 is activated is unknown. Myeloma-derived DKK1, a potent inhibitor of Wnt signaling, binds to the LRP coreceptor on MSCs blocking Wnt signaling, which results in the phosphorylation of β-catenin by GSK3B followed by ubiquination and degradation by the proteasome. The antagonism of Wnt signaling blocks the terminal differentiation of MSCs into osteoblasts. Gregory and colleagues have shown that DKK1 is produced by MSCs and that this induces these cells to reenter the cell cycle (Gregory C, Singh H, Perry AS, et al: The Wnt signaling inhibitor Dickkopf-1 is required for reentry into the cell of human adult stem cells form bone marrow. J Bio Chem 278:28067, 2003). Thus it is possible that the DKK1 made by myeloma plasma cells blocks differentiation and induces proliferation of MSCs. Myeloma plasma cells signal through Wnt and it causes their proliferation (Qiang Y, Endo Y, Rubin JS, et al: Wnt signaling in B-cell neoplasia. Oncogene 22:1536, 2003, Derksen P, Tjin E, Meijer HP, et al: Illegitimate ENT signaling promotes proliferation of multiple myeloma cells. PNAS 101:6122, 2004). It is not clear if the DKK1 may also down regulate Wnt signaling in plasma cells and if this influences myeloma cell proliferation. The osteoblast progenitor cells, but not mature osteoblasts, are a rich source of RANKL (Atkins GJ, Kostakis P, Pan B, et al: RANKL expression is related to the differentiation state of human osteoblasts. J Bone Miner Res 18:1088, 2003), suggesting that the DKK1-mediated block of osteoblast differentiation may also significantly contribute to elevated RANKL in the marrow of myeloma patients. At this stage, plasma cells have an interstitial or mixed interstitial and nodular growth pattern with MRI-defined focal lesions. Although DKK1 expression can be detected in plasma cells that grow interstitially, expression is dramatically reduced or undetectable by immunohistochemistry in cells within focal lesions. During progression, myeloma plasma cells shift from a predominantly interstitial growth pattern (DKK1-positive) to a nodular pattern where large sheets of plasma cells (DKK1-negative) form foci and exhibit aggressive morphologic characteristics (high nuclear-to-cytoplasmic ratio and prominent nucleoli). Downregulation of DKK1 expression accompanies this shift from interstitial to nodular growth. The continued and chronic exposure of the marrow to elevated DKK1 results in overproduction of RANKL and IL-6 by immature osteoblasts and MSCs, and results in the differentiation of osteoclast progenitors into mature bone-resorbing osteoclasts that also produce IL-6. The loss of mature osteoblasts and increase in osteoclasts leads to radiography-detectable lytic bone lesions found exclusively adjacent to nodular plasmacytomas. The downregulation of DKK1 in plasma cells within these nodules is likely a result of direct contact with osteoclasts (Yaccoby S, Wezeman M, Henderson A, Barlogie B, Epstein J: Role and fate of osteoblasts in myeloma. The 9th International Myeloma Workshop. Salamanca, Spain, May 2003. Abstract #149). The molecular means by which osteoclasts extinguish the expression of DKK1 in myeloma plasma cells is currently not known. As disease progresses, interstitial growth gives way to a largely nodular growth pattern, and in the terminal stages of disease, plasma cell growth is highly proliferative and can become extramedullary. Plasma cells derived from virtually all extramedullary stages of myeloma are DKK1-negative. EMG, essential monoclonal gammopathy; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; OAF, osteoclast-activating factors; OPG, osteoprotegerin; PDGF, platelet-derived growth factor; PTHrP, parathyroid hormone-related protein; TGF, transforming growth factor; TNF, tumor necrosis factor. Source: Chapter 109. Myeloma, Williams Hematology, 8e Citation: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT. Williams Hematology, 8e; 2010 Available at: http://accessmedicine.mhmedical.com/DownloadImage.aspx?image=/data/Books/kaus8/kaus8_c109f004a.gif&sec=39853325&BookID=358&ChapterSecID=39835932&imagename= Accessed: October 07, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved