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Previous Volume 349:2483-2494 December 25, 2003 Number 26 Next

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ABSTRACT

Background Myeloma cells may secrete factors that affect the function of osteoblasts, osteoclasts, or both.

Methods We subjected purified plasma cells from the bone marrow of patients with newly diagnosed multiple myeloma and control subjects to oligonucleotide microarray profiling and biochemical and immunohistochemical analyses to identify molecular determinants of osteolytic lesions.

Results We studied 45 control subjects, 36 patients with multiple myeloma in whom focal lesions of bone could not be detected by magnetic resonance imaging (MRI), and 137 patients in whom MRI detected such lesions. Different patterns of expression of 57 of approximately 10,000 genes from purified myeloma cells could be used to distinguish the two groups of patients (P<0.001). Permutation analysis, which adjusts the significance level to account for multiple comparisons in the data sets, showed that 4 of these 57 genes were significantly overexpressed by plasma cells from patients with focal lesions. One of these genes, dickkopf 1 (DKK1), and its corresponding protein (DKK1) were studied in detail because DKK1 is a secreted factor that has been linked to the function of osteoblasts. Immunohistochemical analysis of bone marrow–biopsy specimens showed that only myeloma cells contained detectable DKK1. Elevated DKK1 levels in bone marrow plasma and peripheral blood from patients with multiple myeloma correlated with the gene-expression patterns of DKK1 and were associated with the presence of focal bone lesions. Recombinant human DKK1 or bone marrow serum containing an elevated level of DKK1 inhibited the differentiation of osteoblast precursor cells in vitro.

Conclusions The production of DKK1, an inhibitor of osteoblast differentiation, by myeloma cells is associated with the presence of lytic bone lesions in patients with multiple myeloma.

Source Information

From the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy (E.T., F.Z., B.B., J.D.S.), and the Departments of Radiology (R.W.) and Pathology (Y.M.), College of Medicine, University of Arkansas for Medical Sciences, Little Rock; and Cancer Research and Biostatistics, Seattle (E.R.).

Mr. Tian and Dr. Zhan contributed equally to the article.

Address reprint requests to Dr. Shaughnessy at the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, University of Arkansas for Medical Sciences, 4301 W. Markham St. #776, Little Rock, AR 72205, or at jshaughnessy{at}uams.edu.

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DKK1 in Multiple Myeloma
Meyer M. A., Hofbauer L. C., Neubauer A., Schoppet M., Lu C. M., Walker R. C., Barlogie B., Shaughnessy J. Jr.
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N Engl J Med 2004; 350:1464-1466, Apr 1, 2004. Correspondence

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