scholarly journals The growth fraction of human myeloma cells

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 333-338 ◽  
Author(s):  
B Drewinko ◽  
R Alexanian ◽  
H Boyer ◽  
B Barlogie ◽  
SI Rubinow
Keyword(s):  
Multiple Myeloma ◽  
Growth Kinetics ◽  
Plasma Cells ◽  
Tritiated Thymidine ◽  
High Growth ◽  
Growth Fraction ◽  
Proliferating Cells ◽  
Myeloma Cells ◽  
Tumor Mass ◽  
Kinetics Of

Greater reductions of tumor load in patients with multiple myeloma may result from therapeutic strategies that are based on a better knowledge of growth kinetics. We have previously shown that the labeling index of myeloma cells remains unchanged when tumor mass is reduced and that the cells of relapsing patients have differnt biologic properties than the cells present before melphalan-prednisone therapy. This study investigated the growth fraction (GF) of myeloma cells at various disease stages using continuous i.v. infusions of tritiated thymidine. We studied 17 patients on 22 occasions (4 untreated, 2 unresponsive, 6 in remission, and 10 in relapse). All untreated an unresponsive patients and 5 of 6 patients in remission had a GF of less than 4%. GF was defined in these studies as the maximum percentage of labeled plasma cells exposed continuously to tritiated thymidine. Relapsing patients, with the most rapid tumor doubling times, had GF ranging from 14% to 83%. The plasma cell transit time through the proliferative compartment for all of the relapsing patients ranged from 6.6 to 11.9 days and the calculated intrinsic cell loss ranged from 50% to 86%. These findings support our model for the growth kinetics of multiple myeloma that assumes that the entire tumor mass issues from a small proportion of proliferating cells and that the growth kinetics of myeloma cells in relapsing patterns differ from those in untreated and unresponsive patients. Therapeutic trials with cycle-active agents need further investigation in selected relapsing patients who are likely to have a high growth fraction.

scholarly journals The growth fraction of human myeloma cells

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 333-338 ◽  
Author(s):  
B Drewinko ◽  
R Alexanian ◽  
H Boyer ◽  
B Barlogie ◽  
SI Rubinow
Keyword(s):  
Multiple Myeloma ◽  
Growth Kinetics ◽  
Plasma Cells ◽  
Tritiated Thymidine ◽  
High Growth ◽  
Growth Fraction ◽  
Proliferating Cells ◽  
Myeloma Cells ◽  
Tumor Mass ◽  
Kinetics Of

Abstract Greater reductions of tumor load in patients with multiple myeloma may result from therapeutic strategies that are based on a better knowledge of growth kinetics. We have previously shown that the labeling index of myeloma cells remains unchanged when tumor mass is reduced and that the cells of relapsing patients have differnt biologic properties than the cells present before melphalan-prednisone therapy. This study investigated the growth fraction (GF) of myeloma cells at various disease stages using continuous i.v. infusions of tritiated thymidine. We studied 17 patients on 22 occasions (4 untreated, 2 unresponsive, 6 in remission, and 10 in relapse). All untreated an unresponsive patients and 5 of 6 patients in remission had a GF of less than 4%. GF was defined in these studies as the maximum percentage of labeled plasma cells exposed continuously to tritiated thymidine. Relapsing patients, with the most rapid tumor doubling times, had GF ranging from 14% to 83%. The plasma cell transit time through the proliferative compartment for all of the relapsing patients ranged from 6.6 to 11.9 days and the calculated intrinsic cell loss ranged from 50% to 86%. These findings support our model for the growth kinetics of multiple myeloma that assumes that the entire tumor mass issues from a small proportion of proliferating cells and that the growth kinetics of myeloma cells in relapsing patterns differ from those in untreated and unresponsive patients. Therapeutic trials with cycle-active agents need further investigation in selected relapsing patients who are likely to have a high growth fraction.

Multi-Parameter Flow Cytometry(FC) Can Detect Proliferating Myeloma Cells After Treatment: Implications for Targeting the Myeloma Proliferative Component

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4995-4995
Author(s):  
John Lust ◽  
Shaji Kumar ◽  
Michael Timm ◽  
Kathleen Donovan ◽  
Philip R. Greipp ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Autologous Transplantation ◽  
Cell Labeling ◽  
Growth Fraction ◽  
Proliferating Cells ◽  
Myeloma Cells

Abstract Abstract 4995 Background: Multiple myeloma results from an accumulation of monoclonal nonproliferating plasma cells arising from a small subpopulation of proliferating myeloma cells. In an effort to optimize detection of the human myeloma cell growth fraction and obviate the need for slide review, a novel FC strategy was developed combining elements of light chain restriction, surface antigen expression, and ploidy analysis. Methods: Bone marrow cells from 41 patients with plasma cell proliferative disorders were lysed with ACK and resuspended in 3% BSA. Cells were stained using a 6-color assay with anti-CD45, anti-CD38, anti-CD138, and anti-CD19. Cells were washed and 100 ul Caltag solution A was added for 15 min. Cells were washed and 100 ul of Caltag solution B, anti-kappa and anti-lambda were added for 10 min. Cells were washed and 100 ul PBS and 3 ul RNAse are added for 15 min. Cells were washed and 400 ul of a 1:1000 solution of 3uM DAPI in Tris 0.1% NP-40 was added. Cells were incubated at 4°C for 45 minutes before running on a FACSCanto instrument for ploidy determination. All patients were analyzed both by flow cytometry and the slide based plasma cell labeling index. Results: Forty-one patients were studied; 34 demonstrated a proliferative fraction and 7 had too few plasma cells for analysis after therapy. Of the 34 patients, 6 had MGUS/SMM, 5 newly diagnosed MM, 7 amyloid, and 16 were treated MM. The mean percent proliferating cells were 1.1% (range 0 – 8.6%) with PCLI and 1.4% (range 0.1 – 12.7%) by flow. The correlation between PCLI and flow gave a RSquare value of 0.54. Twelve patients with a PCLI of 0% had a flow proliferation between 0.1 – 1.4% (mean 0.49%). Treated patients received lenalidomide, dexamethasone, bortezomib, and/or autologous transplantation. All 16 treated myeloma patients with adequate plasma cells had a flow proliferation between 0.2 – 12.7% (mean 2.2%). Conclusion: Flow cytometry offers a useful way to detect the proliferative myeloma component at diagnosis and after treatment. The continued presence of proliferating myeloma cells after treatment may explain why most patients relapse and offers another important marker to monitor and cell population to target in patients with active disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

scholarly journals Expansion of the growth fraction in multiple myeloma with alkylating agents

Blood ◽  
1975 ◽  
Vol 45 (1) ◽  
pp. 119-129 ◽  
Author(s):  
SE Salmon
Keyword(s):  
Multiple Myeloma ◽  
Dna Synthesis ◽  
Cytosine Arabinoside ◽  
Cell Kinetics ◽  
Tritiated Thymidine ◽  
Alkylating Agents ◽  
Dynamic Change ◽  
Myeloma Cell ◽  
Growth Fraction ◽  
Myeloma Cells

Abstract Patients with IgG multiple myeloma underwent serial studies of tumor cell kinetics including (1) estimation of the total body myeloma cell number (TBMC), (2) measurement of the myeloma cell tritiated thymidine labeling index (LI), and (3) calculation of the total number of myeloma cells undergoing DNA synthesis. Intermittent courses of chemotherapy with cycle-non-specific agents such as melphalan resulted in a marked increase in the LI of myeloma cells in patients who had a 75% reduction in TBMC. The long “plateau” phase of partial remission of myeloma in these patients was associated with a continued high LI: this suggests that the plateau resulted from a balance between the cytoreductive effects of chemotherapy and expansion of the growth fraction (GF) of the tumor. Preliminary attempts to capitalize therapeutically on this expansion of the GF in several patients included administration of the cycle-active agents vincristine and cytosine arabinoside. Vincristine appeared to induce a further reduction in tumor in several patients, although cytosine arabinoside appeared to be ineffective despite clear evidence of its inhibition of DNA synthesis in myeloma cells in vivo. Further clinical studies of the effects of cycle-active drugs on myeloma appear to be warranted; however, successful exploitation of the dynamic change in myeloma cell kinetics with chemotherapy will require the use of cycle-active agents with marked selective toxicity for myeloma cells.

scholarly journals Expansion of the growth fraction in multiple myeloma with alkylating agents

Blood ◽  
1975 ◽  
Vol 45 (1) ◽  
pp. 119-129
Author(s):  
SE Salmon
Keyword(s):  
Multiple Myeloma ◽  
Dna Synthesis ◽  
Cytosine Arabinoside ◽  
Cell Kinetics ◽  
Tritiated Thymidine ◽  
Alkylating Agents ◽  
Dynamic Change ◽  
Myeloma Cell ◽  
Growth Fraction ◽  
Myeloma Cells

Patients with IgG multiple myeloma underwent serial studies of tumor cell kinetics including (1) estimation of the total body myeloma cell number (TBMC), (2) measurement of the myeloma cell tritiated thymidine labeling index (LI), and (3) calculation of the total number of myeloma cells undergoing DNA synthesis. Intermittent courses of chemotherapy with cycle-non-specific agents such as melphalan resulted in a marked increase in the LI of myeloma cells in patients who had a 75% reduction in TBMC. The long “plateau” phase of partial remission of myeloma in these patients was associated with a continued high LI: this suggests that the plateau resulted from a balance between the cytoreductive effects of chemotherapy and expansion of the growth fraction (GF) of the tumor. Preliminary attempts to capitalize therapeutically on this expansion of the GF in several patients included administration of the cycle-active agents vincristine and cytosine arabinoside. Vincristine appeared to induce a further reduction in tumor in several patients, although cytosine arabinoside appeared to be ineffective despite clear evidence of its inhibition of DNA synthesis in myeloma cells in vivo. Further clinical studies of the effects of cycle-active drugs on myeloma appear to be warranted; however, successful exploitation of the dynamic change in myeloma cell kinetics with chemotherapy will require the use of cycle-active agents with marked selective toxicity for myeloma cells.

Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3354-3362 ◽  
Author(s):  
Niels W. C. J. van de Donk ◽  
Marloes M. J. Kamphuis ◽  
Berris van Kessel ◽  
Henk M. Lokhorst ◽  
Andries C. Bloem
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Mevalonate Pathway ◽  
Cytochrome C Release ◽  
Hmg Coa Reductase ◽  
Myeloma Cells ◽  
Protein Levels ◽  
Geranylgeranyl Transferase ◽  
Induced Apoptosis ◽  
Coa Reductase

AbstractHMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.

scholarly journals Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Laurie Herviou ◽  
Sara Ovejero ◽  
Fanny Izard ◽  
Ouissem Karmous-Gadacha ◽  
Claire Gourzones ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Histone H4 ◽  
Myeloma Cells ◽  
Functional Studies ◽  
Replicative Stress ◽  
Poor Outcome ◽  
Subsequent Decrease ◽  
Lysine Methyltransferase

Abstract Background Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. In addition to a wide panel of genetic mutations, epigenetic alterations also appear as important players in the development of this cancer, thereby offering the possibility to reveal novel approaches and targets for effective therapeutic intervention. Results Here, we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for the mono-methylation of histone H4 at lysine 20, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Primary malignant plasma cells are particularly addicted to the activity of this epigenetic enzyme. Indeed, the inhibition of SETD8 by the chemical compound UNC-0379 and the subsequent decrease in histone H4 methylation at lysine 20 are highly toxic in MM cells compared to normal cells from the bone marrow microenvironment. At the molecular level, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and, as observed in other cancers, triggers an activation of the tumor suppressor p53, which together cause an impairment of myeloma cell proliferation and survival. However, a deadly level of replicative stress was also observed in p53-deficient myeloma cells treated with UNC-0379, indicating that the cytotoxicity associated with SETD8 inhibition is not necessarily dependent on p53 activation. Consistent with this, UNC-0379 triggers a p53-independent nucleolar stress characterized by nucleolin delocalization and reduction of nucleolar RNA synthesis. Finally, we showed that SETD8 inhibition is strongly synergistic with melphalan and may overcome resistance to this alkylating agent widely used in MM treatment. Conclusions Altogether, our data indicate that the up-regulation of the epigenetic enzyme SETD8 is associated with a poor outcome and the deregulation of major signaling pathways in MM. Moreover, we provide evidences that myeloma cells are dependent on SETD8 activity and its pharmacological inhibition synergizes with melphalan, which could be beneficial to improve MM treatment in high-risk patients whatever their status for p53.

Extramedullary Manifestation of Multiple Myeloma (Systemic Plasmacytoma) That Simulates Hemangioma

2000 ◽  
Vol 124 (4) ◽  
pp. 628-631
Author(s):  
Meenakshi A. Nandedkar ◽  
Susan L. Abbondanzo ◽  
Markku Miettinen
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cell ◽  
Mediastinal Mass ◽  
Epithelial Membrane Antigen ◽  
Plasma Cells ◽  
Vascular Tumor ◽  
Unique Type ◽  
Myeloma Cells ◽  
Subcutaneous Nodules ◽  
Morphologic Appearance

Abstract We describe 2 cases of a unique type of extramedullary manifestation of multiple myeloma (systemic plasmacytoma) that presented as subcutaneous nodules and mediastinal mass, respectively. Both lesions had a similar morphologic appearance, with dilated vascular-like lumina that was separated by thin fibrovascular septa, filled with erythrocytes, and lined by mature and immature plasma cells and plasmacytoid cells. The plasma and plasmacytoid lining cells showed κ light chain restriction in both cases, consistent with a B-cell monoclonal process. The lining cells were also focally positive for epithelial membrane antigen but were negative for endothelial cell markers. Abundant delicate capillaries were seen in the septa that separated the vascular lumina, mimicking a vascular tumor. Furthermore, we believe that our cases are different from the previously described blood lakes in a plasmacytoma by the presence of well-formed fibrovascular septa that separated the vascular-like spaces. Neoangiogenesis propagated by myeloma cells may contribute to this unusual morphologic manifestation of extramedullary manifestation of multiple myeloma.

Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 610-618 ◽  
Author(s):  
Inge Tinhofer ◽  
Ingrid Marschitz ◽  
Traudl Henn ◽  
Alexander Egle ◽  
Richard Greil
Keyword(s):  
Multiple Myeloma ◽  
Cell Survival ◽  
Cell Lines ◽  
Plasma Cells ◽  
Constitutive Expression ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Cytotoxic Treatment ◽  
Interleukin 15 ◽  
Induced Apoptosis

Interleukin-15 (IL-15) induces proliferation and promotes cell survival of human T and B lymphocytes, natural killer cells, and neutrophils. Here we report the constitutive expression of a functional IL-15 receptor (IL-15R) in 6 of 6 myeloma cell lines and in CD38high/CD45low plasma cells belonging to 14 of 14 patients with multiple myeloma. Furthermore, we detected IL-15 transcripts in all 6 myeloma cell lines, and IL-15 protein in 4/6 cell lines and also in the primary plasma cells of 8/14 multiple myeloma patients. Our observations confirm the existence of an autocrine IL-15 loop and point to the potential paracrine stimulation of myeloma cells by IL-15 released from the cellular microenvironment. Blocking autocrine IL-15 in cell lines increased the rate of spontaneous apoptosis, and the degree of this effect was comparable to the pro-apoptotic effect of depleting autocrine IL-6 by antibody targeting. IL-15 was also capable of substituting for autocrine IL-6 in order to promote cell survival and vice versa. In short-term cultures of primary myeloma cells, the addition of IL-15 reduced the percentage of tumor cells spontaneously undergoing apoptosis. Furthermore, IL-15 lowered the responsiveness to Fas-induced apoptosis and to cytotoxic treatment with vincristine and doxorubicin but not with dexamethasone. These data add IL-15 to the list of important factors promoting survival of multiple myeloma cells and demonstrate that it can be produced and be functionally active in an autocrine manner.

scholarly journals AUTORADIOGRAPHIC STUDIES ON THE IMMUNE RESPONSE

1962 ◽  
Vol 115 (1) ◽  
pp. 209-230 ◽  
Author(s):  
G. J. V. Nossal ◽  
O. Mäkelä
Keyword(s):  
Immune Response ◽  
Growth Kinetics ◽  
Generation Time ◽  
Doubling Time ◽  
Plasma Cells ◽  
Single Pulse ◽  
Tracer Injection ◽  
Autoradiographic Labeling ◽  
Kinetics Of ◽  
Stimulation Of

The origin and growth kinetics of plasma cells have been investigated using autoradiographic labeling techniques. Rats immunized once with Salmonella flagella were given a single pulse of H3-thymidine 4 or 40 weeks later. 2 hours after the tracer injection, they received a secondary antigenic stimulus. When animals were sacrificed immediately only certain cells from the resting primarily immunized lymph nodes, notably large and medium lymphocytes, were labeled. Subsequent to secondary stimulation, animals were killed at intervals; nearly all the plasma cells formed within the next 5 to 6 days were labeled. They must thus have been the progeny of cells already capable of synthesizing DNA in resting nodes, most probably of large lymphocytes. Plasmacytopoiesis began with little or no lag following secondary immunization, and the number of labeled plasma cells rose exponentially between the 2nd and 4th day, with a doubling time of about 12 hours. Studies of mean grain counts of primitive cells also suggested that the generation time of plasmablasts was 12 hours or less. The hypothesis was proposed that immunological memory depended on the persistence, following primary stimulation, of a continuously dividing stem line of primitive lymphocytes, reactive at all times to further antigenic stimulation.

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