K Iwato

Hiroshima University, Hiroshima-shi, Hiroshima-ken, Japan

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Publications (35)197.32 Total impact

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    ABSTRACT: A 28-year-old man with marked eosinophilia is described. FIP1L1/PDGFRA mRNA showed multiple alternatively-spliced fusion transcripts. Sequencing analysis showed that the deduced DNA breakpoints were intron 10 in the FIP1L1 gene and exon 12 in the PDGFRA gene. Then, a diagnosis of chronic eosinophilic leukemia (CEL) was made. Whereas the response to the treatments with prednisolone and hydroxyurea were unsatisfactory, treatment with imatinib showed a rapid decrease of eosinophils. The hemoglobin level also dropped and bone marrow examination showed pure red cell aplasia. Continued administration of very low dose imatinib (100 mg every 5 days) led to and maintained complete molecular remission, with good tolerability.
    Internal Medicine 01/2010; 49(12):1195-200. · 0.97 Impact Factor
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    ABSTRACT: Three cases of acute leukaemia with t(4;12) (qll-12;pl3) karyotypic abnormalities were analysed. They had the following common clinical and biological characteristics: (1) dysplasia of three haemopoietic lineages; (2) absent or low myeloperoxidase activity; and (3) retention of platelets in the peripheral blood and megakaryocytes in the bone marrow. There were increased numbers of basophils in the bone marrow and peripheral blood in two of the cases. In all, the blast cells displayed the unique immunophenotype CD7+CD13+CD34+HLA-DR+. The blasts analysed in one case expressed c-kit on the membrane surface. These findings suggest that the t(4:12) (qll-12:pl3) abnormality is associated with a particular type of acute leukaemia, one in which the morphology and immunophenotype suggest that the translocation may have occurred at an early stage of haemopoiesis.
    British Journal of Haematology 03/2008; 90(4):850 - 854. · 4.94 Impact Factor
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    ABSTRACT: Thalidomide has been used for the treatment of refractory multiple myeloma, the dosage in Japan is lower than in other countries; however, there is little information on the pharmacokinetics and their relationship with the drug response. The aim of this study was to characterize the pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma, and to examine the relationship between pharmacokinetics and adverse events. On the first and second days, a 100 mg capsule was administered to 8 Japanese patients after breakfast and blood samples were obtained. The plasma concentrations were measured using HPLC and analyzed based on a one-compartment model. If intolerable adverse events were not observed for 14 d, the dose was increased to 200 mg. The average apparent volume of distribution (Vd/F), apparent total clearance (CL/F) and area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity), which were 45.3 l, 5.5 l/h and 21.7 microg.h/ml, respectively, with smaller Vd/F and CL/F and larger AUC0-infinity than in Caucasian populations. This pharmacokinetic difference may explain the dose difference between Japan and other countries. Adverse events were associated with AUC0-infinity, which was best correlated with plasma concentration at 12 h after administration. The 12-h time point was suggested to be a capable indicator for "safety-oriented" therapeutic drug monitoring of thalidomide.
    Biological & Pharmaceutical Bulletin 12/2006; 29(11):2331-4. · 1.85 Impact Factor
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    ABSTRACT: To investigate the relationship between the pattern of methylation at the major breakpoint cluster region (M-BCR) and transformation of chronic myelocytic leukemia (CML) from the chronic to the blastic phase, the M-BCR methylation status was examined serially from chronic to blastic phase in 23 CML patients. The DNA of mononuclear cells from bone marrow or peripheral blood was digested with restriction enzymes HpaII and BglII, and hybridized with a 5'M-BCR probe. The methylation status was stable during evolution of CML from chronic to the myeloid blastic phase. Cells in both phases showed consistent methylation patterns consisting of fully methylated rearranged fragments of variable size, 4.8, 3.1/3.0, and 2.7/2.5 kb. Conversely, there was substantial heterogeneity in methylation patterns in patients with lymphoid crisis. All lymphoid-crisis patients studied in blastic phase showed a pattern distinct from that of the chronic phase in the same patient, as well as from the myeloid pattern, suggesting cell lineage-specific M-BCR methylation. Moreover, in four of six patients with lymphoid crisis, the chronic-phase patterns were different from those of cases with myeloid crisis. Ph-positive and -negative acute lymphocytic leukemia (ALL) showed methylation patterns different from those of lymphoid crisis in CML. Although the number of patients with lymphoid crisis studied has been limited, these results suggest that analysis of M-BCR methylation status may be of clinical use in distinguishing lymphoid from myeloid crises and predicting the cell lineage of a crisis when the disease is still in the chronic phase.
    Cancer Genetics and Cytogenetics 05/2001; 126(2):102-10. · 1.93 Impact Factor
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    ABSTRACT: Thirty-eight sex-mismatched bone marrow transplantation patients with various hematological diseases were followed-up using fluorescence in situ hybridization. Probes specific for various translocations, the X chromosome (DXZ1) and the whole Y chromosome (WCP Y), were used to assess successful engraftment and residual host cells. The combination of translocation and WCP Y probes enabled the identification of host and donor cells in addition to the identification of malignant vs. normal cells in the transplant recipient. Fifteen patients were sequentially followed up. The results obtained using the combination of translocation plus WCP Y probes were more reliable than those with DXZ1 plus WCP Y probes, or the translocation probe alone, especially when the percentage of residual leukemic cells detected by the translocation probe alone was around the cut-off level.
    Japanese journal of cancer research: Gann 05/1997; 88(4):420-6.
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    ABSTRACT: We performed fluorescence in situ hybridization (FISH) upon 9;22 and 15;17 translocation-positive bone marrow cells to monitor the clinical course of 46 patients with chronic myelocytic leukemia (CML) and nine with acute promyelocytic leukemia (AML M3) who received chemotherapy and/or bone marrow transplantation (BMT). M-BCR-ABL and PML-RAR alpha probes were used to detect translocations of t(9;22) and t(15;17), respectively. Signals from CML patients treated with interferon (17 patients) or BMT (29 patients) were 0.5-15% positive for the 9;22 translocation. Among nine M3 patients who received extensive chemotherapy or BMT, 1-5% were positive for the 15;17 translocation. A highly sensitive FISH procedure using both translocation probes and a whole chromosome Y probe was established and applied to eight sex-mismatched BMT patients (seven CML and one AML M3), in which 0.1-0.6% of signals positive for the specific translocations were detected. These results suggested that interphase FISH is powerful enough to identify minor cell populations of 9;22 or 15;17 translocations after therapy, as well as to detect specific chromosome abnormalities at diagnosis.
    Leukemia 04/1997; 11(3):436-40. · 10.16 Impact Factor
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    ABSTRACT: Three cases of acute leukaemia with t(4;12) (q11-12;p13) karyotypic abnormalities were analysed. They had the following common clinical and biological characteristics: (1) dysplasia of three haemopoietic lineages: (2) absent or low myeloperoxidase activity: and (3) retention of platelets in the peripheral blood and megakaryocytes in the bone marrow. There were increased numbers of basophils in the bone marrow and peripheral blood in two of the cases. In all, the blast cells displayed the unique immunophenotype CD7+CD13+CD34+HLA-DR+. The blasts analysed in one case expressed c-kit on the membrane surface. These findings suggest that the t(4;12) (q11-12;p13) abnormality is associated with a particular type of acute leukaemia, one in which the morphology and immunophenotype suggest that the translocation may have occurred at an early stage of haemopoiesis.
    British Journal of Haematology 09/1995; 90(4):850-4. · 4.94 Impact Factor
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    ABSTRACT: With regard to the expression of adhesion molecules, human myeloma cells freshly isolated from bone marrow were heterogeneous. By two-color analysis with anti-VLA-5 antibody (PE staining) and FITC-labeled anti-CD38 antibody, we found all myeloma cells located at CD38-strong positive (CD38++) fraction and identified two subpopulations among these myeloma cells: CD38++ VLA-5-(VLA-5-) myeloma cells and CD38++ VLA-5+ (VLA-5+) myeloma cells. To clarify the biologic character of these two subpopulations, the morphology, in vitro proliferative activity and in vitro M-protein secretion were examined in each fraction isolated by the purification procedure or a cell sorter. Morphologic examination showed that VLA-5- myeloma cells were mostly immature or plasmablastic and VLA-5+ cells were mature myeloma cells. Furthermore, VLA-5- myeloma cells proliferated markedly in vitro and responded to interleukin 6 (IL-6), a growth factor for myeloma cells, while VLA-5+ myeloma cells showed very low uptakes of 3H-thymidine and no responses to IL-6 but secreted higher amounts of M-protein (immunoglobulin) in vitro significantly. Therefore, we could clarify here heterogeneity of human myeloma cells in the bone marrow with regard to the expression of VLA-5, one of integrin adhesion molecules; VLA-5- myeloma cells were proliferative immature cells and VLA-5+ cells were mature myeloma cells.
    Blood 08/1993; 82(2):564-70. · 9.78 Impact Factor
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    ABSTRACT: We have recently shown that two-color analysis with fluorescein isothiocyanate (FITC)-anti-CD38 antibody could clearly distinguish myeloma cells (plasma cells) from other hematopoietic cells in the bone marrow. Myeloma cells (plasma cells) alone were located at CD38strong positive (++) fractions. To further distinguish normal plasma cells from mature myeloma cells phenotypically, we examined immunophenotypes of normal plasma cells and myeloma cells by two-color flow cytometry with FITC-anti-CD38 antibody and phycoerythrin staining with antibody to VLA-4, MPC-1, CD44, CD56, CD19, CD20, CD24, or CD10. Normal plasma cells were all VLA-4+VLA-5+MPC-1+CD44+ CD19+CD56- in the bone marrows from seven healthy donors, tonsils from four patients with chronic tonsillitis, a spleen from one patient with idiopathic thrombocytopenic purpura, and lymph nodes from two patients with chronic lymphadenitis, respectively. On the other hand, mature myeloma cells (12 of 20 cases), VLA-4+VLA-5+MPC-1+, were all CD19- and most of them CD56+, and there were no myeloma cells with the CD19+CD56- phenotype in the 20 cases of myelomas we tested. Thus, as for the expression of CD19 and CD56, normal plasma cells from various tissues are all CD19+CD56-, whereas no myeloma cells have the CD19+CD56- phenotype. According to this finding, we investigated the expression of CD19 and CD56 on plasma cells (CD38++ fractions) in monoclonal gammopathy of undetermined significance (MGUS). Both CD19+CD56- and CD19-DC56+ plasma cells were found in all five cases of MGUS we tested, suggesting that MGUS consists of phenotypically normal plasma cells and myeloma cells. Therefore, it is reasoned that phenotypic analysis of plasma cells with anti-CD19 and anti-CD56 antibodies can distinguish normal plasma cells from malignant plasma cells (myeloma cells), and can detect malignant plasma cells even in MGUS or premyeloma states.
    Blood 06/1993; 81(10):2658-63. · 9.78 Impact Factor
  • K Iwato, M M Kawano
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    ABSTRACT: Heterogenous biological character of myeloma cells was associated with different expression of adhesion molecules. Myeloma cells could be phenotypically divided into two subpopulations: CD38++/VLA5+/MPC-1+(VLA-5+) cells and CD38++/VLA5-/MPC-1-(VLA-5-) cells. VLA-5- myeloma cells were morphologically immature and proliferated markedly with response to IL-6 in vitro, while VLA-5+ cells showed very low uptakes of 3H-TdR but secreted higher amounts of M-protein in vitro. These results suggest VLA-5- cells are proliferative precursor in myeloma. With respect to VLA-5 and MPC-1 expression, myeloma precursor cells (CD38++/VLA-5-/MPC-1-/CD10-/CD24-) showed similar phenotype to germinal center B cells (CD38+/VLA-5-/MPC-1-/CD10+/CD24-), rather than that of pre-B cells in the bone marrow (CD38+/VLA-5+/MPC-1-/CD10+/CD24+). Identification of precursor cells and characterization of their growth is important for the understanding of pathophysiology of myeloma and the therapeutic strategy.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 05/1993; 34(4):433-8.
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    ABSTRACT: In order to clarify the mechanism of drug resistance in human myeloma cells, we investigated the expressions of DNA topoisomerase I and topoisomerase II gene and the genes possibly related to drug resistance; multi-drug resistant gene 1 (MDR-1), glutathione S-transferase class pi gene (GST-pi), by Northern blotting. Myeloma cells in eight of 15 cases prior to chemotherapy expressed topoisomerase I mRNA considerably, while the expression of topoisomerase II mRNA was detected weakly in only one of 16 myeloma patients. There was not any correlation between expression of topoisomerase I mRNA and clinical drug resistance. Significant expression of MDR-1 mRNA and P-glycoprotein was not detected in 25 cases of multiple myeloma prior to chemotherapy and even after several courses of VAD (vincristine, adriamycin and dexamethasone) therapy by Northern blotting and immunostaining using monoclonal anti-P-glycoprotein antibody (MRK-16), respectively. On the other hand, 16 of 21 myeloma cases showed significant expression of GST-pi protein and GST-pi mRNA with the various strengths, but there was no apparent correlation between GST-pi mRNA expression and clinical response. Therefore these data suggest that expression of the genes we tested may not determine the level of drug resistance in multiple myeloma, but lower or no significant expression of topoisomerase II mRNA in most myeloma cells indicates the possibility that topoisomerase II inhibitors such as VP-16 and topoisomerase II-mediated cytotoxic drugs such as adriamycin, are not so effective for the treatment of multiple myeloma.
    British Journal of Haematology 02/1993; 83(1):68-74. · 4.94 Impact Factor
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    ABSTRACT: Using highly purified myeloma cells from patient bone marrow, we established human-murine myeloma chimeras in severe combined immunodeficiency (SCID) mice and documented secretion of monoclonal human immunoglobulins (Hulgs) in the mice for up to 299 days. Monoclonality of circulating Hulgs was found only when highly purified myeloma cells were injected intraperitoneally. In contrast, injection of unfractionated myeloma marrow led to the development of polyclonal Hulgs in the SCID mice. The criteria for myeloma engraftment included prolonged presence of monoclonal Hulgs in the sera of SCID mice and/or detection of human myeloma cells in their tissues by immunohistochemical examination. Ninety-one percent (10/11) of the fresh purified myeloma specimens engrafted in the SCID mice. Fifty-five percent (6/11) of the patient samples resulted in human B-cell grafts, and 45% (5/11) were identifiable as human myeloma chimeras. Pathologic studies showed that most human plasmacytes were located in the peritoneal cavity but metastatic infiltrates were also found in other organs in 69% of the SCID-human myeloma chimeras. This chimeric model should provide a useful tool for characterization of growth modulation and microenvironmental interactions as well as a means of testing new therapeutic approaches to multiple myeloma.
    Blood 01/1993; 80(11):2843-50. · 9.78 Impact Factor
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    ABSTRACT: Untreated twenty patients of multiple myeloma were treated with the chemotherapy protocol as follows: Initial induction therapy;MP continuous or MP intermittent----IFN alpha----steroid pulse. Maintenance therapy;alkylating agents which have no cross resistance were used ((V) MP----(MP)----(V) EP----MCNU). Remission rate (CR+PR) after the initial MP therapy was 45%, and that after including IFN alpha and steroid pulse therapy was 50%, Fifty percent survival rate was almost as same as those reported previously (34M). Our protocol presented here was based on the idea that, initially, myeloma cells with proliferative activity could be affected by MP therapy, and subsequent IFN alpha therapy would have effect even on the residual myeloma cells. Serial checks of 3H-TdR uptake of myeloma cells during the therapy supported this idea. During the maintenance therapy, clinical responses to the initial induction therapy were not aggravated in the responded cases when evaluated by the variation of serum M-protein level. We propose that considering from a point of proliferative activity of myeloma cells is important for designing therapeutic protocols for multiple myeloma.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 06/1992; 33(5):655-61.
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    ABSTRACT: Alteration and abnormal expression of the c-myc oncogene were investigated in human multiple myeloma. Human myeloma cells were highly purified (more than 95%) from bone marrow aspirates in 14 cases of advanced multiple myelomas and one case of plasma cell leukaemia. Southern blotting revealed that a rearranged configuration of c-myc gene was found in only one case of them, but this was a novel truncation of the gene in its coding exon II; a rearranged 3.4 kb band was detected by digestion with Xba I using c-myc exon II probe, but no rearranged band was found using exon III probe. In this case, the truncated c-myc allele was not transcribed; normal sized (2.4 kb) c-myc mRNA was markedly expressed, but no aberrant mRNA was detected. On the other hand, by Northern blotting, the nine cases, including the case with the rearranged c-myc gene, showed increased expression of normal sized (2.4 kb) c-myc mRNA. Elevated c-myc mRNA expressions were well related to the in vitro proliferation (3H-TdR uptake), but not to IL-6 response. Interestingly, extremely high expressions of c-myc mRNA were detected in two cases of aggressive myelomas, including the case with the rearranged c-myc gene, and in one of plasma cell leukaemia. These two cases of aggressive myelomas were the ones who showed the markedly high 3H-TdR uptakes, and had the common clinical features with the formation of an extramedullary mass and very short survival. These results suggest that the activation of c-myc gene could induce high proliferative activities and the subsequent aggressive transformation of myeloma cells.
    British Journal of Haematology 05/1991; 77(4):523-8. · 4.94 Impact Factor
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    ABSTRACT: Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL-6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature 332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1 beta rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1 beta mRNA and markedly suppressed the bone resorbing activity induced by IL-1 beta OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1 beta OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.
    Blood 03/1990; 75(3):715-20. · 9.78 Impact Factor
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    ABSTRACT: The effects of interferon-alpha (IFN alpha) on in vitro proliferation and M-protein secretion in human myeloma cells were investigated. Human myeloma cells were purified from bone marrow aspirates in 12 multiple myeloma patients. Purified myeloma cells were cultured for 48 hours with IFN alpha at its lower concentrations (0.1 to 100 U/mL). The cells were then pulsed with 3H-TdR for the last 12 hours and 3H-TdR uptake was measured (in vitro proliferation). After 48-hour culture, supernatants were harvested and the amount of M-protein in these fluids were measured by enzyme-linked immunosorbent assay (ELISA) (in vitro M-protein secretion). In vitro M-protein secretions of myeloma cells were significantly suppressed even at 0.1 U/mL of IFN alpha, while 3H-TdR uptakes were not so suppressed until 10 or 100 U/mL of IFN alpha were added. The expressions of secretory immunoglobulin (Ig) mRNA of these myeloma cells were also selectively suppressed by IFN alpha. Furthermore, after IFN alpha had been administered intramuscularly, 3 to 6 x 10(6) U/d for at least 1 month, in vitro M-protein secretions of these myeloma cells were decreased compared with those before IFN alpha administration. Therefore, these results suggest that IFN alpha has more sensitive inhibitory effect on M-protein secretion of human myeloma cells rather than on myeloma cell proliferation.
    Blood 11/1989; 74(5):1718-22. · 9.78 Impact Factor
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    ABSTRACT: Human myeloma cells were highly purified from bone marrow aspirates of 21 patients with advanced immunoglobulin G (IgG)-type multiple myeloma. B-cell stimulatory factor 2 (BSF-2)/interleukin-6 (IL-6) was originally characterized as a cytokine that can enhance immunoglobulin secretion from activated normal B cells and increase the expression of secretory-type Ig mRNA in these B cells, but that does not augment proliferation of activated B cells. However, recombinant IL-6 (rIL-6) could not enhance M-protein (IgG) secretion in freshly isolated myeloma cells in vitro but could augment proliferation of myeloma cells, although myeloma cells constitutively expressed IL-6 receptors. Furthermore, expression of secretory-type IgG (gamma-chain) mRNA in myeloma cells was not changed in the presence of IL-6. These results show that IL-6 is not an enhancing factor in Ig secretion from myeloma cells, and thus signal transduction through IL-6 in myeloma cells may be altered as opposed to activated B cells.
    American Journal of Hematology 09/1989; 31(4):258-62. · 4.00 Impact Factor
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    ABSTRACT: Supernatants of freshly isolated human myeloma cell cultures were examined both for bone-resorbing activity (BRA) in vitro using newborn mouse calvaria, and for identification of the causal substances of the BRA. Eight of 14 culture supernatants of myeloma cells had BRA. All of these BRA-positive supernatants were from patients with marked destructive bone lesions of multiple myeloma. The presence of interleukin 1 (IL-1), especially IL-1 beta, was demonstrated in seven of these BRA-positive supernatants but not in BRA-negative supernatants. The concentrations of IL-1 beta were high enough to induce bone resorption in the newborn mouse calvaria assay and the BRA was totally abolished by pretreatment of the supernatants with anti-IL-1 beta antibody but not with either anti-IL-1 alpha antibody or normal serum. Other bone resorbing cytokines such as tumor necrosis factor or lymphotoxin were not present in high enough concentrations to stimulate bone resorption and their levels did not correlate with the BRA. IL-1 beta mRNA was also identified in BRA-positive myeloma cells. These results demonstrate that IL-1 beta is the principal agent of BRA present in supernatants of myeloma cell cultures, and also identify a possible role of IL-1 beta in destructive bone lesions in patients with multiple myeloma.
    Cancer Research 09/1989; 49(15):4242-6. · 8.65 Impact Factor
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    ABSTRACT: Recombinant interleukin 1 alpha (rIL-1 alpha) augmented proliferation of freshly isolated myeloma cells as well as B-cell stimulatory factor 2 (BSF-2)/interleukin-6 (IL-6). Recombinant IL-1 alpha-induced proliferation was partially inhibited by anti-IL-6 antibody. In the culture supernatants of rIL-1 alpha-stimulated myeloma cells, IL-6 activities, which were measured by using an IL-6-dependent murine hybridoma clone, MH60.BSF2, were increased, when compared with those in the culture supernatants of nonstimulated myeloma cells. Furthermore, IL-6 messenger RNA (mRNA) expression was also augmented in IL-1 alpha-stimulated myeloma cells. Therefore rIL-1 alpha stimulates myeloma cells to produce IL-6, which consequently augments proliferation of myeloma cells. Thus, IL-1 can accelerate autocrine growth of myeloma cells through IL-6.
    Blood 07/1989; 73(8):2145-8. · 9.78 Impact Factor
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    ABSTRACT: Human myeloma cells were purified from bone marrow aspirates from four patients having advanced myeloma, including one with common acute lymphoblastic leukemia antigen-positive myeloma. All of these myelomas had marked bone lytic lesions. From the culture supernatants of these purified myeloma cells, bone-resorbing activities were significantly revealed by 45Ca-release bone resorption assay, and IL-1 activities were also detected by IL-1 bioassay (mouse thymocyte comitogenic assay). Sandwich enzyme immunoassay for IL-1 alpha or IL-1 beta revealed that IL-1 beta was responsible for IL-1 activity of these culture supernatants. Furthermore, the bone resorbing activities of these culture supernatants were completely neutralized by pretreatment of anti-IL-1 beta, but not anti-IL-1 alpha antibody. By Northern blot analysis, IL-1 beta mRNA was identified from these myeloma cells. Therefore, it is concluded that myeloma cells produce IL-1 beta, which acts as bone-resorbing activity in multiple myeloma.
    Blood 06/1989; 73(6):1646-9. · 9.78 Impact Factor

Publication Stats

2k Citations
197.32 Total Impact Points

Institutions

  • 1988–2001
    • Hiroshima University
      • • Research Institute for Radiation Biology and Medicine (RIRBM)
      • • Department of General Internal Medicine
      Hiroshima-shi, Hiroshima-ken, Japan