DKK1 in Multiple Myeloma
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The color image accompanying the editors' summary of the article by Tian et al. (Dec. 25 issue)1 provides information that would be helpful in any future study on dickkopf 1 (DKK1) gene expression in multiple myeloma. The image is a whole-body 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic (PET) scan with extensive evidence of marrow involvement; more than 60 lesions are identified. PET has been shown to be a sensitive indicator of disease in multiple myeloma2; in another study,3 71 bone lesions not seen on plain-film radiography were detected in 14 of 41 patients with multiple myeloma. PET imaging could be incorporated into future clinical and research studies of multiple myeloma. In the study by Tian et al., the 7th and 32nd of 36 patients in whom no lesions were seen on magnetic resonance imaging (MRI) or plain-film radiography in fact had significant DKK1 expression. Future investigations of multiple myeloma with gene microarray profiling would probably be improved with the use of the quantitative information provided by PET imaging. DKK1 expression may be correlated with the volume, or burden, of disease as calculated according to PET data.
Michael A. Meyer, M.D.
Buffalo Cardiology and Pulmonary Associates
Buffalo, NY 14221
michaelandrewmeyer@yahoo.com
References
Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483-2494.
Jadvar H, Conti PS. Diagnostic utility of FDG PET in multiple myeloma. Skeletal Radiol 2002;31:690-694.
Schirrmeister H, Bommer M, Buck AK, et al. Initial results in the assessment of multiple myeloma using 18F-FDG PET. Eur J Nucl Med Mol Imaging 2002;29:361-366.
To the Editor: By applying microarray techniques, Tian et al. identified DKK1 as a myeloma-derived, secreted inhibitor of the differentiation of osteoblasts from mesenchymal precursor cells. This blockade results in a decrease in bone formation that is inadequate to match enhanced bone resorption in patients with myeloma bone disease. Moreover, DKK1-mediated arrest of osteoblast differentiation results in an increase in the ratio of receptor activator of nuclear factor-B ligand (RANKL) to osteoprotegerin within the bone microenvironment; this change enhances osteoclastic bone resorption and promotes the formation of osteolytic bone lesions.1
Since myeloma cells express RANKL, and since RANKL expression positively correlates with osteolytic bone disease in patients with multiple myeloma,2 it would be of interest to know whether RANKL or other components of the RANKL–osteoprotegerin cytokine system were identified or found to be differentially expressed in the microarray. Cytogenetic abnormalities are important prognostic variables in myeloma.3 According to the information in Table 1 of the article by Tian et al., cytogenetic abnormalities (mainly deletion or hypodiploidy of chromosome 13) were substantially more common in patients with bone lesions than in those without such lesions. Was DKK1 expression related to cytogenetic abnormalities or a particular cytogenetic aberration?
Lorenz C. Hofbauer, M.D.
Andreas Neubauer, M.D.
Michael Schoppet, M.D.
Philipps University
D-35033 Marburg, Germany
hofbauer@post.med.uni-marburg.de
References
Sezer O, Heider U, Zavrski I, Kühne CA, Hofbauer LC. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003;101:2094-2098.
Heider U, Langelotz C, Jakob C, et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003;9:1436-1440.
Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101:4569-4575.
To the Editor: Tian et al. compared the gene-expression profiles of myeloma cells from patients with and those without focal osteolytic lesions and found that the Wnt-signaling antagonist DKK1 has a critical role in the development of osteolytic lesions in multiple myeloma. They also found overexpression of three other genes — the genes encoding dihydrofolate reductase, proteasome activator subunit, and CDC28 protein kinase — in myeloma cells from patients with bone lesions.
It is important to recognize the role of DKK1,1 an inhibitor of osteoblast differentiation, in the pathogenesis of osteolytic lesions in multiple myeloma. On the other hand, the roles of osteoclast-activating factors2 (such as RANKL,3 parathyroid hormone–related protein, macrophage inflammatory protein 1, and interleukin-1) in the formation of osteolytic lesions have been well established. However, the authors do not mention the levels of expression of these osteoclast-activating factors. I would like to know whether the genes encoding these factors were included in the analysis of the microarrays used in the study and, if so, their levels of expression.
Chuanyi M. Lu, M.D.
University of California, San Francisco, School of Medicine
San Francisco, CA 94121
mark.lu@med.va.gov
References
Glass DA II, Patel MS, Karsenty G. A new insight into the formation of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2479-2480.
Callander NS, Roodman GD. Myeloma bone disease. Semin Hematol 2001;38:276-285.
Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 2003;63:5438-5445.
The authors reply: The image Dr. Meyer refers to is an 18F-FDG PET scan showing more than 60 focal bone lesions in multiple myeloma. The results of MRI and 18F-FDG PET studies correlated with long-term prognosis and spurred us to investigate the molecular mechanism underlying the development of these focal lesions. Dr. Meyer mentions the prospect of correlating both functional imaging and early assessment of the response to treatment in multiple myeloma with gene microarray profiling. Using 18F-FDG PET, Durie et al.1 distinguished monoclonal gammopathy of undetermined significance (MGUS) from myeloma; detected conversion from MGUS to myeloma, active myeloma, and extramedullary disease; predicted early relapse; and detected new disease in patients with relapses. In their study, focal lesions developed within three months after base line in two patients with elevated DKK1 levels but no focal lesions.
Genes that encode known osteoclast-activating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL1, were on the microarrays we used. However, we were unable to identify a significant relation between the expression of an osteoclast-activating factor or related factor by myeloma plasma cells and the presence of bone disease. In microarray analyses on plasma cells from more than 300 patients with newly diagnosed myeloma, we have not seen significant expression of RANKL (unpublished data). Since the expression of RANKL by myeloma cells is controversial,2,3,4,5 we also tested RANKL expression by quantitative reverse-transcriptase–polymerase-chain-reaction analysis in 48 cases from this study. RANKL was undetectable in 50 percent of the cases and only marginally detectable in the remaining 50 percent. The MIP1 and PTHrP genes were expressed in myeloma plasma cells and showed a high degree of variability among patients with myeloma, yet this variability could not be related to the presence of lytic lesions. We have not recognized a link between any particular chromosomal abnormality and DKK1 expression.
Ronald C. Walker, M.D.
Bart Barlogie, M.D., Ph.D.
John Shaughnessy, Jr., Ph.D.
University of Arkansas for Medical Sciences
Little Rock, AR 72205
jshaughnessy@uams.edu
References
Durie BG, Waxman AD, D'Aglono A, Williams CM. Whole-body 18F-FDG PET identifies high-risk myeloma. J Nucl Med 2002;43:1457-1463.
Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 2003;63:5438-5445.
Heider U, Langelotz C, Jakob C, et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003;9:1436-1440.
Giuliani N, Colla S, Sala R, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood 2002;100:4615-4621.
Barille-Nion S, Bataille R. New insights in myeloma-induced osteolysis. Leuk Lymphoma 2003;44:1463-1467.
Michael A. Meyer, M.D.
Buffalo Cardiology and Pulmonary Associates
Buffalo, NY 14221
michaelandrewmeyer@yahoo.com
References
Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483-2494.
Jadvar H, Conti PS. Diagnostic utility of FDG PET in multiple myeloma. Skeletal Radiol 2002;31:690-694.
Schirrmeister H, Bommer M, Buck AK, et al. Initial results in the assessment of multiple myeloma using 18F-FDG PET. Eur J Nucl Med Mol Imaging 2002;29:361-366.
To the Editor: By applying microarray techniques, Tian et al. identified DKK1 as a myeloma-derived, secreted inhibitor of the differentiation of osteoblasts from mesenchymal precursor cells. This blockade results in a decrease in bone formation that is inadequate to match enhanced bone resorption in patients with myeloma bone disease. Moreover, DKK1-mediated arrest of osteoblast differentiation results in an increase in the ratio of receptor activator of nuclear factor-B ligand (RANKL) to osteoprotegerin within the bone microenvironment; this change enhances osteoclastic bone resorption and promotes the formation of osteolytic bone lesions.1
Since myeloma cells express RANKL, and since RANKL expression positively correlates with osteolytic bone disease in patients with multiple myeloma,2 it would be of interest to know whether RANKL or other components of the RANKL–osteoprotegerin cytokine system were identified or found to be differentially expressed in the microarray. Cytogenetic abnormalities are important prognostic variables in myeloma.3 According to the information in Table 1 of the article by Tian et al., cytogenetic abnormalities (mainly deletion or hypodiploidy of chromosome 13) were substantially more common in patients with bone lesions than in those without such lesions. Was DKK1 expression related to cytogenetic abnormalities or a particular cytogenetic aberration?
Lorenz C. Hofbauer, M.D.
Andreas Neubauer, M.D.
Michael Schoppet, M.D.
Philipps University
D-35033 Marburg, Germany
hofbauer@post.med.uni-marburg.de
References
Sezer O, Heider U, Zavrski I, Kühne CA, Hofbauer LC. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003;101:2094-2098.
Heider U, Langelotz C, Jakob C, et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003;9:1436-1440.
Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003;101:4569-4575.
To the Editor: Tian et al. compared the gene-expression profiles of myeloma cells from patients with and those without focal osteolytic lesions and found that the Wnt-signaling antagonist DKK1 has a critical role in the development of osteolytic lesions in multiple myeloma. They also found overexpression of three other genes — the genes encoding dihydrofolate reductase, proteasome activator subunit, and CDC28 protein kinase — in myeloma cells from patients with bone lesions.
It is important to recognize the role of DKK1,1 an inhibitor of osteoblast differentiation, in the pathogenesis of osteolytic lesions in multiple myeloma. On the other hand, the roles of osteoclast-activating factors2 (such as RANKL,3 parathyroid hormone–related protein, macrophage inflammatory protein 1, and interleukin-1) in the formation of osteolytic lesions have been well established. However, the authors do not mention the levels of expression of these osteoclast-activating factors. I would like to know whether the genes encoding these factors were included in the analysis of the microarrays used in the study and, if so, their levels of expression.
Chuanyi M. Lu, M.D.
University of California, San Francisco, School of Medicine
San Francisco, CA 94121
mark.lu@med.va.gov
References
Glass DA II, Patel MS, Karsenty G. A new insight into the formation of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2479-2480.
Callander NS, Roodman GD. Myeloma bone disease. Semin Hematol 2001;38:276-285.
Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 2003;63:5438-5445.
The authors reply: The image Dr. Meyer refers to is an 18F-FDG PET scan showing more than 60 focal bone lesions in multiple myeloma. The results of MRI and 18F-FDG PET studies correlated with long-term prognosis and spurred us to investigate the molecular mechanism underlying the development of these focal lesions. Dr. Meyer mentions the prospect of correlating both functional imaging and early assessment of the response to treatment in multiple myeloma with gene microarray profiling. Using 18F-FDG PET, Durie et al.1 distinguished monoclonal gammopathy of undetermined significance (MGUS) from myeloma; detected conversion from MGUS to myeloma, active myeloma, and extramedullary disease; predicted early relapse; and detected new disease in patients with relapses. In their study, focal lesions developed within three months after base line in two patients with elevated DKK1 levels but no focal lesions.
Genes that encode known osteoclast-activating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL1, were on the microarrays we used. However, we were unable to identify a significant relation between the expression of an osteoclast-activating factor or related factor by myeloma plasma cells and the presence of bone disease. In microarray analyses on plasma cells from more than 300 patients with newly diagnosed myeloma, we have not seen significant expression of RANKL (unpublished data). Since the expression of RANKL by myeloma cells is controversial,2,3,4,5 we also tested RANKL expression by quantitative reverse-transcriptase–polymerase-chain-reaction analysis in 48 cases from this study. RANKL was undetectable in 50 percent of the cases and only marginally detectable in the remaining 50 percent. The MIP1 and PTHrP genes were expressed in myeloma plasma cells and showed a high degree of variability among patients with myeloma, yet this variability could not be related to the presence of lytic lesions. We have not recognized a link between any particular chromosomal abnormality and DKK1 expression.
Ronald C. Walker, M.D.
Bart Barlogie, M.D., Ph.D.
John Shaughnessy, Jr., Ph.D.
University of Arkansas for Medical Sciences
Little Rock, AR 72205
jshaughnessy@uams.edu
References
Durie BG, Waxman AD, D'Aglono A, Williams CM. Whole-body 18F-FDG PET identifies high-risk myeloma. J Nucl Med 2002;43:1457-1463.
Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res 2003;63:5438-5445.
Heider U, Langelotz C, Jakob C, et al. Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003;9:1436-1440.
Giuliani N, Colla S, Sala R, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood 2002;100:4615-4621.
Barille-Nion S, Bataille R. New insights in myeloma-induced osteolysis. Leuk Lymphoma 2003;44:1463-1467.