What Is Important Factor of Bone Disease in Multiple Myeloma?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4855-4855
Author(s):  
Shoso Munemasa ◽  
Akira Sakai ◽  
Yoshiko Okikawa ◽  
Yoshiaki Kuroda ◽  
Yuta Katayama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cyclin D1 ◽  
Bone Disease ◽  
Tissue Growth ◽  
Good Survival ◽  
Bone Lesions ◽  
Rt Pcr ◽  
Myeloma Cells ◽  
Significant Difference ◽  
Chromosome 13Q

Abstract New International Prognostic Index (IPI) staging system of multiple myeloma (MM) is a combination of the level of serum β2-microglobulin and serum albumin. Particularly, good survival (median survival >5 years) is associated with absence of chromosome 13q deletion. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. We have reported that some MM cases with cyclin D1 overexpression detected by competitive RT-PCR were not caused by t(11;14)(q13;q32) or extra copies of 11q13 (In J Oncol, in press). A recent report revealed that subtypes of MM cases with the translocation of cyclin D showed a close correlation with bone disease and high level of DKK1. We also have been studing about the correlation between bone disease and bone morphogenetic protein (BMP) 2, or connective tissue growth factor (CTGF) that is supposed to inhibit the VEGF binding to its receptor or modulate cell signaling by BMP. First, we analyzed IPI staging in 91 MM cases, and then analyzed the relation between IPI staging and existence of cyclin D1 overexpression, or t(11;14)(q13;q32) and extra copies of 11q13. Competitive RT-PCR was performed in 77 cases, and cyclin D1 overexpression was detected in 40/77 (52%). Deletion of chromosome 13q was detected in 32/87 (37%), and t(11;14)(q13;q32) or extra copies of 11q13 was detected in 11/50 (22%) and 7/50 (14%), respectively. There were no significant differences of those factors among IPI staging. And we analyzed the scale of bone lesion by bone x-ray in 81 cases. We could not detect the relation between bone disease and cyclin D1 overexpression or translocation of 11q13. Furthermore, we analyzed the expression of BMP2 and CTGF by quantitative real time-PCR in purified myeloma cells or in bone marrow mononuclear cells (BMMNC) reduced myeloma cells less than 5%. We have gotten results that MM cases have a tendency to show higher CTGF expression in BMMNC compared with that of normal BM, but there was no significant difference of BMP2 expression in BMMNC between them. And there was no correlation between cyclin D1 overexpression and BMP2 or CTGF expression. So far a cause of bone lesions in MM is supposed to be the activity of osteoclast, however, our preliminary examination by TRAP staining revealed that osteoclast differentiation from BMMNC in MM cases by adding M-CSF (25 ng/ml) and RANKL (50 ng/ml) decreased compared with that in normal BM, and osteoblast diffentiation also decreased in MM by cytochemical staining for alkaline phosphatase (AP). We guess that both osteoclast and osteobalst differentiation are suppressed in MM and CTGF is a candidate for the suppressor of osteoblast differentiation. We will be able to show the result of AP activity of osteoblast and the effect of recombinant CTGF on osteoblast in meeting.

Connective Tissue Growth Factor (CTGF) Is an Indicator of Bone Involvement in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5025-5025
Author(s):  
Shoso Munemasa ◽  
Akira Sakai ◽  
Yoshiaki Kuroda ◽  
Yoshiko Okikawa ◽  
Yuta Katayama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Connective Tissue ◽  
Bone Disease ◽  
Osteoblast Differentiation ◽  
Tissue Growth ◽  
Bone Involvement ◽  
Osteoprogenitor Cells ◽  
Myeloma Cells ◽  
Significant Difference

Abstract Bone disease in multiple myeloma (MM) is due to not only the activation of osteoclasts but also the impairment of osteoblast differentiation. Recent studies showed the overexpression of the Wnt signaling antagonists FRZB (secreted Frizzled-related protein 3, sFRP-3) and dickkopf1 (DKK1) is important in MM-related bone disease. Bone morphogenetic proteins (BMPs) and connective tissue growth factor (CTGF) are known to play essential roles in promoting the proliferation of early osteoprogenitor cells, specifically, differentiation from mesenchymal stem cells (MSC) to committed osteoprogenitor cells. Expression of CTGF is reported to be up-regulated by Wnt3A or BMPs stimulation. CTGF has four domains each of which participates in macromolecular interactions that are relevant to CTGF action as a modulating factor. In particular, Domain 2 is known to bind BMPs and thus block downstream signalling. The two N- and C-half domains are connected by a central hinge region which is protease sensitive. Some matrix metalloproteinases (MMP-2, 3, 7, 13) cleave this region. Study of clinical samples has shown that a major form of CTGF in the circulation is the N-half fragment. We analyzed the concentration of circulating CTGF in 39 patients with MM and 22 patients with malignant lymphoma (ML). Full length CTGF and N-half CTGF + full length CTGF in patient serum samples were detected and quantitated by separate sandwich ELISAs. The level of N-half CTGF was significantly higher in patients with MM compared to patients with ML (these subjects have normal BM) (p<0.001). Furthermore, serum content of N-half CTGF was significantly higher (p<0.001) in MM patients with bone disease compared to those without bone involvement. This may relate to BMP effects on bone physiology. Perhaps the CTGF N-half-fragment is a more effective BMP antagonist than intact CTGF. Alternatively, N-half CTGF may be less potent than intact CTGF for promoting osteoblast differentiation. First, we expected that cutting CTGF by MMP-13 produced by myeloma cells might be a cause of bone disease in MM. However, although the expression of MMP-13 was detected in myeloma cells by RT-PCR, cytoplasmic MMP-13 was positive only in MM patients with progressive disease (PD), and the level of serum MMP-13 was less than the sensitivity by ELISA. Furthermore, we analyzed the level of serum MMP-9 because it reportedly plays a role in the activation of osteoclasts. However, there was no significant difference between patients with MM and ML, and also no difference between MM patients with and without bone disease. We did not detect a significant difference of MMP9 expression between MM patients with and without bone disease by RQ-PCR. These results suggest that CTGF, N-half CTGF or both play a role in MM to promote bone involvement. In addition, evaluation of CTGF and CTGF fragments may serve as a useful approach to evaluate disease progression. The cause of high CTGF N-half-fragment in patients with MM should be clarified.

Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3518-3518
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Peter Liebisch ◽  
Susanne Rötzer ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Conventional Radiography ◽  
Bone Lesions ◽  
X Rays ◽  
Myeloma Bone Disease ◽  
Lytic Lesions ◽  
Significant Difference ◽  
First Time

Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

scholarly journals An Improved Animal Model of Multiple Myeloma Bone Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-31
Author(s):  
Syed Mehdi ◽  
Maurizio Zangari ◽  
Donghoon Yong
Keyword(s):  
Multiple Myeloma ◽  
Lumbar Spine ◽  
Bone Disease ◽  
Therapeutic Effects ◽  
Myeloma Cells ◽  
Tail Vein ◽  
Significant Difference ◽  
Osteolytic Bone Disease ◽  
Nsg Mouse

Multiple myeloma (MM) is a plasma cell malignancy that represents an accumulation of terminally differentiated monoclonal plasma cells (PCs) in the bone marrow (BM), accompanied by increased osteoclasts and decreased osteoblasts in areas adjacent to myeloma cells, leading to MM associated bone disease (MMBD). Osteolytic bone disease is one of the defining features of MM. During the disease, over 90% of patients are developing MMBD. Many of MM animal models have been developed and enable us to interrogate the mechanisms of MM tumorigenesis. Most MMBD models were derived by intratibial injection of myeloma cells. In these models, osteolysis occurs locally at the site where myeloma cells were injected. Mouse myeloma cells, 5TGM1 transplanting C57BL/KaLwRij mouse via the tail vein develops and shows MMBD features close to human MMBD. Even in this model, the MMBD levels on each mouse are widely varied. Lack of appropriate in vivo MMBD model hampers our understanding of the disease and developing therapy. We try to establish a murine model for MMBD to study its pathophysiology and test a novel treatment. 1x106 luciferase-expressing 5TGM1 (5TGM1-Luc) cells were injected into 8-12 week old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was weekly assessed by in vivo bioluminescence (BL) imaging using IVIS-200 (Perkin Elmer). Mice were sacrificed when they showed endpoint signals such as significant weight loss, hindlimb paralysis, etc.. At postmortem, the micro-computer tomography (micro-CT) was performed for bone histo-morphometric analyses using micro CT400, Scano medical, Inc. The median survival was 56 days in NSG, while 42 days in C57BL/KaLwRij. In vivo BL image analysis showed that myeloma slowly develops in NSG mouse in comparison to C57BL/KaLwRij mouse. Histomorphic analyses found that severe osteolytic lesions occur at the lumbar spine in NSG mouse compared to C57BL/KaLwRij mouse, but no significant difference at the femur of both strains. At the lumbar spine, trabecular thickness (p &lt; 0.0004) and trabecular space (p &lt; 0.0014) were significantly increased in NSG mouse compared to C57BL/KaLwRij mouse. On the contrary, trabecular number (p &lt; 0.0002) and bone volume density (p &lt; 0.0005) were significantly decreased in NSG mouse compared to C57BL/KaLwRij mouse. In conclusion, we found that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than C57BL/KaLwRij model. This model will serve a better MMBD model to evaluate the therapeutic effects of MMBD targeted drugs. Disclosures No relevant conflicts of interest to declare.

Heparanase Expression Correlates with Bone Destruction in the Patients with Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1813-1813 ◽  
Author(s):  
Shi Wei ◽  
Racquel Innis-Shelton ◽  
Li Nan ◽  
Jian Ruan ◽  
Rebecca S Sollie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Bone Marrow Cells ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Bone Marrow Biopsies ◽  
Myeloma Cells ◽  
Lytic Bone Lesions ◽  
Marrow Cells

Abstract Abstract 1813 Multiple myeloma is an incurable malignancy, and excessive bone destruction is a major cause of morbidity in myeloma patients. However, the biologic mechanisms involved in the pathogenesis of myeloma-induced bone disease are poorly understood. Heparanase, an enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of human tumors, including myeloma. In the present study, bone marrow biopsies from 40 myeloma patients were stained with antibodies raised against heparanase, RANKL (an osteoclastogenic cytokine), OPG (a decoy receptor for RANKL), TRAP (a marker of osteoclastogenesis) and osteocalcin (a marker of osteoblastogenesis). The radiologic studies for bone lesions of these patients were also recorded. We analyzed the correlations between heparanase expression in bone marrow myeloma cells with (1) the numbers of TRAP positive osteoclasts, (2) RANKL and OPG expression in myeloma cells and osteoblastic cells, (3) the numbers of osteocalcin positive osteoblasts in bone marrow, and (4) the presence/absence of lytic bone lesions. We found a positive correlation between heparanase expression and RANKL expression as well as the numbers of TRAP positive osteoclasts in myeloma and bone marrow cells, but no correlation was found between the expressions of heparanase and OPG in bone marrow cells (myeloma cells do not express OPG). In contrast, heparanase expression was negatively correlated with the numbers of osteocalcin positive osteoblasts. Taken together, these data suggest that heparanase expression by myeloma cells promotes osteoclastogenesis and at same time inhibits osteoblastogenesis. Clinical data show that 92% of patients with high level of heparanase had one or more lytic bone lesions, while only 63% of patients with median∼ low levels of heparanase had bone lesions (p<0.0001). In summary, enhanced heparanase expression in myeloma cells promotes bone resorption and inhibits bone formation; these events contribute to the uncontrolled bone destruction that is characteristic of myeloma. These data provide novel insight into the mechanisms driving myeloma bone disease and suggest that heparanase inhibitors are valid therapeutic targets for the treatment of multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

scholarly journals Comparison of the diagnostic performance and impact on management of 18F-FDG PET/CT and whole-body MRI in multiple myeloma

2021 ◽  
Author(s):  
Olwen Westerland ◽  
◽  
Ashik Amlani ◽  
Christian Kelly-Morland ◽  
Michal Fraczek ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Data ◽  
Bone Disease ◽  
Fdg Pet ◽  
Diagnostic Performance ◽  
Whole Body ◽  
Bone Lesions ◽  
Pet Ct ◽  
18F Fdg ◽  
Fdg Pet Ct

Abstract Purpose Comparative data on the impact of imaging on management is lacking for multiple myeloma. This study compared the diagnostic performance and impact on management of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and whole-body magnetic resonance imaging (WBMRI) in treatment-naive myeloma. Methods Forty-six patients undergoing 18F-FDG PET/CT and WBMRI were reviewed by a nuclear medicine physician and radiologist, respectively, for the presence of myeloma bone disease. Blinded clinical and imaging data were reviewed by two haematologists in consensus and management recorded following clinical data ± 18F-FDG PET/CT or WBMRI. Bone disease was defined using International Myeloma Working Group (IMWG) criteria and a clinical reference standard. Per-patient sensitivity for lesion detection was established. McNemar test compared management based on clinical assessment ± 18F-FDG PET/CT or WBMRI. Results Sensitivity for bone lesions was 69.6% (32/46) for 18F-FDG PET/CT (54.3% (25/46) for PET component alone) and 91.3% (42/46) for WBMRI. 27/46 (58.7%) of cases were concordant. In 19/46 patients (41.3%) WBMRI detected more focal bone lesions than 18F-FDG PET/CT. Based on clinical data alone, 32/46 (69.6%) patients would have been treated. Addition of 18F-FDG PET/CT to clinical data increased this to 40/46 (87.0%) patients (p = 0.02); and WBMRI to clinical data to 43/46 (93.5%) patients (p = 0.002). The difference in treatment decisions was not statistically significant between 18F-FDG PET/CT and WBMRI (p = 0.08). Conclusion Compared to 18F-FDG PET/CT, WBMRI had a higher per patient sensitivity for bone disease. However, treatment decisions were not statistically different and either modality would be appropriate in initial staging, depending on local availability and expertise.

scholarly journals International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease

2013 ◽  
Vol 31 (18) ◽  
pp. 2347-2357 ◽  
Author(s):  
Evangelos Terpos ◽  
Gareth Morgan ◽  
Meletios A. Dimopoulos ◽  
Matthew T. Drake ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Multiple Myeloma ◽  
Spinal Cord Compression ◽  
Bone Disease ◽  
Working Group ◽  
Cord Compression ◽  
Vertebral Compression Fractures ◽  
Bone Lesions ◽  
Published Data ◽  
International Myeloma Working Group

PurposeThe aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) –related bone disease.MethodologyAn interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members.RecommendationsBisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Expression of the CD117 Antigen on Multiple Myeloma and Its Significance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4867-4867
Author(s):  
Juan Li ◽  
Shaokai Luo ◽  
Guocai Zhang ◽  
Wende Hong ◽  
Xiuzhen Tong
Keyword(s):  
Multiple Myeloma ◽  
Tyrosine Kinase ◽  
Selective Inhibitors ◽  
Differentiation Antigen ◽  
Color Flow ◽  
Myeloma Cells ◽  
Significant Difference ◽  
Theoretical Evidence ◽  
Highly Correlated

Abstract BACKGROUND & OBJECTIVE: Leukocyte differentiation antigen CD117 is one of the targets that tyrosine kinase selective inhibitors work on. CD117, whether the cell surface is expressed and the quality of its expression, is highly correlated with the tyrosine kinase selective inhibitors. And whether Multiple myeloma (MM) cells express CD117 and its expression quality is not reported domestic yet but only several reported overseas. In this study, CD117 expressed in MM cells is evaluated, which provide an theoretical evidence for tyrosine kinase selective inhibitors used in the MM, meanwhile, the value of the CD117 expressed in MM cells is estimated. METHODS:CD117,CD56,CD54 were measured by three -color flow cytometry with CD45/SSC gating strategy. RESULTS:Of 48 patients with MM, 17(35.5%) CD117 expression was positive in myeloma cells, and CD56, CD54 expression was positive in 39(81.2%), 48(100.0%), respectively. CD117 expression in myeloma cells was low compared with CD56, CD54 in 48 patients with MM; CD117 positive expression showed a positive correlation with myeloma cells in the bone marrow; CD117 positive in IgG type of MM was 64%, higher than other types such as light chain or IgA.CD117 positive showed no significant difference in different stage, untreated, relapsed and refractory patients (P&gt;0.05, P&gt;0.01); In untreated MM patient, chemotherapy of VAD in CD117 positive patient, the effectiveness was 71.4%, compared with the reaction rate 66.7% in CD117 negative, showed no significant difference (P&gt;0.05). CONCLUSIONS:CD117 &lt;/SU

Angiopoietin-1 and Osteopontin Expression by CD138+ Myeloma Cells Rather Than VEGF and CD45 Correlates with Bone Marrow Angiogenesis in Multiple Myeloma Patients at the Diagnosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2501-2501
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Francesca Morandi ◽  
Sabrina Bonomini ◽  
Mirca Lazzaretti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Linear Trend ◽  
The Other ◽  
Vegf Mrna ◽  
Myeloma Cells ◽  
Other Hand ◽  
Significant Difference ◽  
Angiopoietin 1

Abstract Bone marrow (BM) angiogenesis is increased in Multiple Myeloma (MM) patients and correlates with disease progression and patient survival. Myeloma cells secrete the main endothelial growth factor VEGF. In mouse models VEGF secretion as well as the angiogenic properties of MM cells correlate with the lack of CD45 expression by MM cells. However, recent data indicate that VEGF plasma cell expression is similar between MGUS and MM patients suggesting that other molecules could be involved. In line with this hypothesis we have recently demonstrated that myeloma cells may also produce factors with angiogenic properties as angiopoietin-1 (ANG-1) and osteopontin (OPN) that are involved in myeloma induced angiogenesis in vitro. In order to identify which factors correlate with BM angiogenesis in MM patients, we have investigated in a cohort of 121 newly diagnosed MM patients (stage I–III) the expression of the angiogenic molecules VEGF, ANG-1 and OPN and their correlation with bone marrow (BM) angiogenesis and CD45 expression by MM cells. We found that 90% of CD138+ MM cells tested were positive for VEGF mRNA. On the other hand we found that 50% and 40 % of MM patients were positive for ANG-1 and OPN mRNA respectively. Using the previously published cut off for CD45 expression we found that 61 out of 121 MM patients were positive for CD45 and 60 out of 121 were negative for CD45 expression. Any correlation was not observed between VEGF expression and BM angiogenesis in MM patients (p=0.5), whereas the number of microvessels X field was higher in Ang-1 positive patients in comparison with Ang-1 negative ones (mean±SE: 6.23±0.2 vs. 2.94±0.1, median: 6.21 vs. 2.79; p=0.001,) and the microvascular density (MVD) was significantly increased (32.98±1.7 vs. 14.55±1.3, median: 34.69 vs. 13.04; p&lt;0.01; capillaries: 26.73±1.3 vs. 10.42±0.8, median: 24.06 vs. 9.04; p&lt;0.01, small venules: 9.56 ±0.5 vs. 4.14±0.5, median: 10.60 vs. 3.65; p&lt;0.01). Furthermore a significantly positive correlation between Ang-1 expression and MVD was found (Pearson Chi-square: p=0.036, Cochran’s Linear Trend: p=0.01). A significantly higher MVD was also observed in the group of patients positive for OPN, (mean±SE: 29.1±0.7 vs. 17.55±0.37; p&lt;0.01) and similarly, the number of microvessels per field was higher in OPN positive patients in comparison with OPN negative ones (mean±SE: 6.7±0.15 vs. 4.28±0.04; p=0.05). On the other hand, any significant difference was not observed between CD45 positive and CD45 negative patients for the expression of VEGF (p=0.4), ANG-1 (p=0.3) and OPN (p=0.09). Consistently we did not find any significant difference in both MVD and number of vessels X field between CD45 positive patients as compared with CD45 negative ones (p=0.5 and p=0.4, respectively). Finally, a multivariate analysis confirmed that VEGF and CD45 did not correlate with the BM angiogenesis showing that ANG-1 expression by MM cells was more tightly correlated with MVD and the number of vessels X field as compared to OPN. Our data indicate that ANG-1 and in part OPN rather than VEGF and CD45 expression by MM cells are the critical determinants correlated with the increase of BM angiogenesis that occurs in MM patients at the diagnosis.

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