The Immunotoxin HM1.24-ETA′ Is a Potent Inducer of Apoptosis in Malignant Plasma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3658-3658
Author(s):  
Matthias Staudinger ◽  
Anja Muskulus ◽  
Renate Burger ◽  
Andreas Guenther ◽  
Roland Repp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Annexin V ◽  
Myeloma Cell ◽  
Parp Cleavage ◽  
Single Chain ◽  
Potent Inducer ◽  
Promising Target

Abstract Despite new treatment modalities, the clinical outcome of at least a subgroup of patients with multiple myeloma (MM) still needs improvement. Antibody-based targeted therapies are increasingly used for tumor therapy, and may represent interesting options for MM patients. HM1.24 is a surface molecule that is over expressed on malignant plasma cells and efficiently internalized from the cell surface. It may represent a promising target for the development of myeloma-directed immunoconstructs. Here, the development and characterization of a novel single-chain immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of an HM1.24-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). The immunotoxin was expressed in E. coli and purified to homogeneity by affinity chromatography. Specific binding to HM1.24 was demonstrated by immunofluorescence staining and flow cytometry using antigen positive and negative cells. HM1.24-ETA′ efficiently inhibited growth of IL-6 dependent and IL-6 independent myeloma cell lines (INA-6, RPMI8226, U266). Half maximal growth inhibition was observed at low nanomolar concentrations. Further analyses demonstrated that target cell killing occurred via induction of apoptosis, as evidenced by Annexin V/propidium iodide staining and detection of PARP cleavage. The cytotoxic effect was completely blocked by adding excess of unconjugated parental antibody, demonstrating that the effect was antigen-specific and not mediated by non-specific uptake of the immunotoxin. Importantly, HM1.24-ETA′ efficiently triggered apoptosis (>80% Annexin V positive cells) of freshly isolated plasma cell leukemia cells within 48h. In conclusion, HM1.24-ETA′ efficiently triggered apoptosis of multiple myeloma cell lines as well as freshly isolated tumor cells. These results indicate that HM1.24 may represent a promising target structure for efficient antigen-specific delivery of cytotoxic compounds to plasma cell tumors.

The CD317-Targeted Immunotoxin HM1.24-ETA′ Efficiently Eliminates Malignant Plasma Cells in Vitro and in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1838-1838
Author(s):  
Matthias Staudinger ◽  
Pia Glorius ◽  
Christian Kellner ◽  
Andreas Guenther ◽  
Roland Repp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Annexin V ◽  
Treatment Modalities ◽  
Parp Cleavage ◽  
Target Cells ◽  
Single Chain ◽  
Promising Target

Abstract Abstract 1838 Despite new treatment modalities, the clinical outcome of at least a subgroup of patients with multiple myeloma still needs improvement. Recently antibody-based targeted therapies with a toxic payload have documented impressing activity. HM1.24 (CD317), a surface molecule overexpressed on malignant plasma cells, is efficiently internalized and may represent a promising target for the development of myeloma-directed immunoconstructs. Here, the generation and characterization of a novel single-chain immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). The immunotoxin was expressed in E. coli and the protein was purified to homogeneity by affinity chromatography. HM1.24-ETA′ efficiently inhibited growth of myeloma cell lines (INA-6, RPMI8226, U266) analyzed in MTT assays. Half maximal growth inhibition was observed at low nanomolar concentrations. Target cell killing occurred via induction of apoptosis as indicated by annexin V / propidium iodide staining and analysis of PARP cleavage. The delivery of HM1.24-ETA′ to target cells is antigen-specific, because excess of unconjugated parental antibody completely blocked the cytotoxic effect. The proliferation of IL-6 dependent INA-6 was efficiently reduced by HM1.24-ETA′ even in co-culture experiments with bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA′ strongly triggered apoptosis (up to 80% annexin V-positive cells) of freshly isolated tumor cells from 5 of 5 myeloma patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA′ immunotoxin (p < 0.04). Thus, HM1.24-ETA′ immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of multiple myeloma using immunoconjugates with toxic payloads. Disclosures: No relevant conflicts of interest to declare.

Fully Retargeted Oncolytic Measles Virus for Multiple Myeloma Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5474-5474
Author(s):  
Horst D. Hummel ◽  
Gaby Kuntz ◽  
Takafumi Nakamura ◽  
Axel Greiner ◽  
Stephen J. Russell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Cell Lines ◽  
Plasma Cell ◽  
Measles Virus ◽  
Plasma Cells ◽  
Treatment Modalities ◽  
Single Chain ◽  
Gfp Expression ◽  
Frequent Relapses

Abstract Multiple Myeloma (MM) is a disseminated plasma cell malignancy with approximately 14,600 new cases diagnosed in the USA annually. Despite recent progress in current therapeutical options the median survival is 3 to 5 years and cure is extremely rare. Therefore the evaluation of new treatment modalities for MM is highly warranted. An attractive approach to treat Myeloma with a minimum of undesired side effects is the use of a tumour antigen specific for MM cells. Wue-1, a monoclonal antibody binds very selectively normal and malignant plasma cells (50 of 51 MM samples, 14 of 15 immunocytoma and 13 of 13 MALT type lymphomas with plasma cell differentiation were Wue-1 positive, normal tissue including hematopoietic cells were negative) and offers the possibility to define MM cells as targets. The tool for selective killing of MM cells recognized by Wue-1 monoclonal antibody is in this study the measles virus vaccine strain Edmonston B in an ablated variant (MV-Wue) which no longer binds the usual measles receptors CD46 and CD150 (SLAM) expressed on almost every human cell type displaying a single-chain antibody (scFv) derived from the monoclonal Wue-1-antibody which has been tethered to the C-terminus of the H protein to restrict and retarget its interaction to malignant plasma cells especially MM cells. In addition, MV-Wue encodes EGFP facilitating the read out of infected cells. To determine if the fully retargeted MV-Wue would be able to infect MM cell lines and primary MM cells selectively an array of infection assays were performed using the MM cell lines U266 as well as primary CD138 positive MM cells expressing the Wue-1 antigen as expected targets and CD138 negative cells and normal B cells as controls negative for Wue-1. In these experiments selective infections of the MM cell line and primary MM cells were observed whereas the control cells were not infected with MV-Wue. In all cell types GFP expression indicating replicative infection correlated with the expression of the Wue-1 antigen determined by FACS. Infection experiments performed in the presence of monoclonal Wue-1 antibody showed a decreased GFP expression of about 78% in CD138 positive MM cells demonstrating specificity of the infection by MV-Wue. These results indicate that the engineered virus can be a safe and potential curative oncolytic agent to face the main problem in Multiple Myeloma which is responsible for frequent relapses, the minimal residual disease (MRD).

Inhibition of Interleukin-6 Signaling with CNTO 328 Sensitizes Plasma Cell Dyscrasias to the Effects of Melphalan in Association with Suppression of Signaling through Protein Kinase B/Akt.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1836-1836
Author(s):  
Sally A. Hunsucker ◽  
Valeria Magarotto ◽  
Jairo A. Matthews ◽  
Michael Wang ◽  
Veerabhadran Baladandayuthapani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Cell Lines ◽  
Plasma Cell ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Protein Kinase B ◽  
Myeloma Cell ◽  
Ortho Biotech ◽  
Plasma Cell Dyscrasias

Abstract Abstract 1836 Poster Board I-862 Background: The neutralizing anti-interleukin (IL)-6 monoclonal antibody (MAb) CNTO 328 acts in an additive to synergistic manner to enhance the activity of bortezomib and dexamethasone against models of multiple myeloma by suppressing several IL-6-induced anti-apoptotic signaling pathways. We therefore sought to evaluate the possibility that blockade of IL-6 signaling could also augment the activity of melphalan, and to determine the potential mechanisms underlying this interaction. Methods: A panel of myeloma cell lines was studied both in suspension and with bone marrow stromal cells to evaluate the activity of CNTO 328 with and without melphalan. The CNTO 328 + melphalan combination was also tested in primary cells from patients with a variety of plasma cell dyscrasias. Results: Treatment of IL-6-dependent KAS-6/1, INA-6, and ANBL-6 myeloma cell lines with CNTO 328 + melphalan reduced plasma cell viability in an additive-to-synergistic manner compared to melphalan with a control MAb. Isobologram analysis demonstrated that the combination was synergistic in KAS-6/1 cells regardless of the sequence of drug treatment (combination indices (CIs) from 0.275-0.607), although the strongest synergy was seen with CNTO 328 pretreatment (CIs from 0.275-0.493). These anti-proliferative effects were accompanied by an enhanced activation of drug-specific apoptosis, and this increased cell death was not rescued by the trophic effects of co-culture of plasma cells with the human-derived stromal cell line HS-5. CNTO 328 increased melphalan-mediated induction of both extrinsic, caspase-8-mediated apoptosis, as well as intrinsic, caspase-9-mediated death, which converged to produce increased levels of caspase-3 activity. Apoptosis was enhanced in part by CNTO 328-stimulated cleavage of Bid to tBid, and alterations in the phosphorylation status of BimEL, as well as increased conversion of Bak and, to a lesser extent, of Bax, to their active forms. Neutralization of IL-6 by CNTO 328 also suppressed signaling through the protein kinase B/Akt pathway, as evidenced by decreased levels of phospho-Akt, and decreased activation of several downstream Akt targets, including p70 S6 kinase and 4E-BP1. Importantly, CNTO 328 + melphalan showed enhanced anti-proliferative effects compared to melphalan and a control MAb against primary CD138+ plasma cells derived from patients with multiple myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis, while demonstrating less toxicity to stromal cells. The enhanced effect of the CNTO 328 + melphalan combination was statistically significant compared to either drug alone (p<0.05) in CD138+ cells isolated from patients who had not received prior melphalan therapy. Conclusions: These studies provide a rationale for translation of CNTO 328 into the clinic in combination with melphalan-based therapies, including either high dose therapy in transplant-eligible patients, or standard dose melphalan-containing induction regimens in transplant-ineligible patients, such as with the combination of bortezomib, melphalan, and prednisone. Disclosures: Voorhees: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau. Xie:Centocor Ortho Biotech Inc.: Employment. Cornfeld:Centocor Ortho Biotech Inc.: Employment. Nemeth:Centocor Ortho Biotech Inc.: Employment.

A Novel Role for Histone Deacetylase 11 (HDAC11) in B Cell Lymphopoiesis and Plasma Cell Survival in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4715-4715
Author(s):  
Jason B. Brayer ◽  
Eva Sahakian ◽  
John Powers ◽  
Mark B Meads ◽  
Susan Deng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Proteasome Inhibitors ◽  
Myeloma Cell ◽  
Resistant Cell ◽  
Rpmi 8226 ◽  
Human Myeloma Cell

Abstract While multiple myeloma (MM) remains incurable presently, expanded therapeutic options over the past decade have improved patient survival markedly. Proteasome inhibitors have redefined the treatment paradigm for myeloma, often serving as the backbone of front-line treatment. Histone deacetylase (HDAC) inhibitors (HDI), although only marginally active as single agent therapy in hematological malignancies, have demonstrated an ability to salvage bortezomib responsiveness in refractory patients, prompting heightened interest in this class of targeted therapeutics in myeloma. HDAC’s represent a family of enzymes, currently with 11 known members in the classical HDAC family, and subdivided into 4 sub-classes. HDAC11 is currently the only member of the sub-class IV and, as the newest member of the HDAC family, its impact on B cell lymphopoiesis and myeloma development is only starting to be unveiled. Intriguingly, we show that mice with germ-line silencing of HDAC11 (HDAC11KO mice) exhibit a 50% decrease in plasma cells in both the bone marrow and peripheral blood plasma cell compartments relative to wild-type mice. Consistent with this, Tg-HDAC11-eGFP mice, a transgenic strain engineered to express GFP under control of the HDAC11 promoter (Heinz, N Nat. Rev. Neuroscience 2001) reveals that HDAC11 expression is increased in the plasma cell population and to a lesser extent B1 B cells, as compared to earlier lineage stages. Similar observations based on measurements of HDAC11 mRNA were seen in normal human plasma cells. Significant increases in HDAC11 mRNA expression were observed in 7 of 11 primary human multiple myeloma samples and 11 of 12 human myeloma cell lines as compared to normal plasma cells, further emphasizing the potential relevance of HDAC11 to the underlying pathologic processes driving myeloma development and/or survival. Targeted silencing of HDAC11 in RPMI-8226 cells lines using siRNA results in a modest decrease in cell viability as measured by Annexin/PI staining and detection of activated caspase-3. Quisinostat, a second generation pan-HDI, has previously demonstrated activity against human myeloma cell lines in vitro (Stuhmer, Brit J Haematol, 2010), and suppressed bone destruction in an in vivo murine myeloma model (Deleu, Cancer Res, 2009). We similarly observe dose-dependent survival impairment in 10 human myeloma cell lines when cultured in the presence of quisinostat, with EC50’s consistently in the 1-10nM range. Importantly, quisinostat acts synergistically with proteasome inhibitiors (bortezomib and carfilzomib) in RPMI-8226 cells; more importantly, the degree of synergism is amplified in the RPMI-6226-B25 bortezomib-resistant cell line. Although a clear mechanism of action remains to be elucidated, preliminary data suggests that RPMI-8226 cells exposed to quisinostat appear to exhibit a decrease nuclear, but not cytosolic HDAC11. Collectively, these data illustrate a previously unknown role for HDAC11 in plasma cell differentiation and survival. Increased HDAC11 expression seen in myeloma patient specimens and primary myeloma cell lines highlights the potential of HDAC11 as a therapeutic target. Furthermore, we show that quisinostat, a pan-HDI with selectivity towards HDAC11 at lower dosing, acts synergistically with proteasome inhibitors in vitro in proteasome inhibitor sensitive and resistant cell lines. Future work will focus on further elucidating the role of HDAC11 in myeloma survival and drug response, with particular emphasis on proteasome inhibitors. Disclosures No relevant conflicts of interest to declare.

Preclinical activity of the JAK1/2 inhibitor ruxolitinib on malignant plasma cell growth and survival.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18565-e18565 ◽  
Author(s):  
Renate Burger ◽  
Tim Bugdahn ◽  
Matthias Staudinger ◽  
Matthias Peipp ◽  
Andreas Günther ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Thymidine Uptake ◽  
Jak Inhibitor ◽  
Growth And Survival ◽  
Stat3 Phosphorylation

e18565 Background: In multiple myeloma, cytokines in the tumor environment, in particular interleukin-6 (IL-6), support the growth and survival of malignant plasma cells. Binding of IL-6 to its receptor leads to gp130 dimerization and activation of JAKs and STAT3. Ruxolitinib (INC424)is the first small molecule JAK inhibitor approved for the treatment of patients with myelofibrosis. The aim of our study was to evaluate the effects of ruxolitinib on malignant plasma cells. Methods: Cell growth was studied in seven myeloma cell lines including the IL-6 dependent INA-6. Ruxolitinib was tested at 0.0625 µmol/L to 8 µmol/L. Proliferation of plasma cell enriched patient samples was measured by [3]H-thymidine uptake, apoptosis by flow cytometry upon annexin V/7-AAD staining. Levels of STAT3 and ERK1/2 phosphorylation were determined by Westernblot analysis. IC50 concentrations and combination index were calculated with CalcuSyn. IL-6 levels were determined by ELISA. Results: A significant inhibition of plasma cell growth with ruxolitinib was achieved in IL-6 dependent INA-6 cells (IC50 0.22 µmol/L). Complete growth inhibition at 1 µmol/L was seen in the absence and presence of bone marrow stromal cells. Stromal cell viability and IL-6 production were not affected. The number of apoptotic INA-6 cells upon treatment with ruxolitinib at 1 µmol/L increased 3.6- and 7.2-fold (after 48 and 72 hours, respectively), consistent with the reduction of IL-6 induced STAT3 phosphorylation. A similar strong inhibitory activity of ruxolitinib (IC50 0.16 µmol/L) was observed in tumor cells of a patient with plasma cell leukemia proliferating in response to IL-6. In contrast, none of the myeloma cell lines that grow autonomously were sensitive, pointing to the kinase specificity of the drug. Using INA-6 as a model, combinations with other signaling inhibitors revealed additive to synergistic effects with PI3K, mToR and IGF-1R inhibitors. Conclusions: In multiple myeloma, ruxolitinib has a strong cytotoxic activity against malignant plasma cells that require IL-6 for growth and survival. This warrants further clinical testing but also points to the need of identifying molecular markers to predict benefit from JAK inhibitor treatment.

Ruxolitinib Regulates the Autophagy Machinery in Multiple Myeloma Cells

2020 ◽  
Vol 20 (18) ◽  
pp. 2316-2323 ◽  
Author(s):  
Alican Kusoglu ◽  
Bakiye G. Bagca ◽  
Neslihan P.O. Ay ◽  
Guray Saydam ◽  
Cigir B. Avci
Keyword(s):  
Multiple Myeloma ◽  
Cell Line ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Annexin V ◽  
Myeloma Cell ◽  
Control Group ◽  
Multiple Myeloma Cell ◽  
Ic50 Values ◽  
Stat Pathway

Background: Ruxolitinib is a selective JAK1/2 inhibitor approved by the FDA for myelofibrosis in 2014 and nowadays, comprehensive investigations on the potential of the agent as a targeted therapy for haematological malignancies are on the rise. In multiple myeloma which is a cancer of plasma cells, the Interleukin- 6/JAK/STAT pathway is emerging as a therapeutic target since the overactivation of the pathway is associated with poor prognosis. Objective: In this study, our purpose was to discover the potential anticancer effects of ruxolitinib in ARH-77 multiple myeloma cell line compared to NCI-BL 2171 human healthy B lymphocyte cell line. Methods: Cytotoxic effects of ruxolitinib in ARH-77 and NCI-BL 2171 cells were determined via WST-1 assay. The autophagy mechanism induced by ruxolitinib measured by detecting autophagosome formation was investigated. Apoptotic effects of ruxolitinib were analyzed with Annexin V-FITC Detection Kit and flow cytometry. We performed RT-qPCR to demonstrate the expression changes of the genes in the IL-6/JAK/STAT pathway in ARH-77 and NCI-BL 2171 cells treated with ruxolitinib. Results: We identified the IC50 values of ruxolitinib for ARH-77 and NCI-BL 2171 as 20.03 and 33.9μM at the 72nd hour, respectively. We showed that ruxolitinib induced autophagosome accumulation by 3.45 and 1.70 folds in ARH-77 and NCI-BL 2171 cells compared to the control group, respectively. Treatment with ruxolitinib decreased the expressions of IL-6, IL-18, JAK2, TYK2, and AKT genes, which play significant roles in MM pathogenesis. Conclusion: All in all, ruxolitinib is a promising agent for the regulation of the IL-6/JAK/STAT pathway and interferes with the autophagy mechanism in MM.

scholarly journals Phenotypic analysis of human myeloma cell lines

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 566-572
Author(s):  
C Duperray ◽  
B Klein ◽  
BG Durie ◽  
X Zhang ◽  
M Jourdan ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Light Chains ◽  
Cell Phenotype ◽  
Phenotypic Analysis ◽  
Barr Virus ◽  
Human Myeloma Cell

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation, primarily in bone marrow, of a clone of plasma cells. The nature of the stem cells feeding the tumoral compartment is still unknown. To investigate this special point, we have studied the phenotypes of nine well-known human myeloma cell lines (HMCLs) and compared them with those of normal lymphoblastoid cell lines (LCLs). Twenty-four clusters of differentiation involved in B lymphopoiesis were investigated using a panel of 65 monoclonal antibodies (MoAbs). For each cluster, the percentage of positive cells and the antigen density were determined, giving rise to a “quantitative phenotype”. We thus classified the HMCLs into two different groups: those with cytoplasmic mu chains (c mu+) and those without (c mu-). In the first (c mu+) group, comprising seven cell lines, the HMCLs had a phenotype of pre-B/B cells close to that of Burkitt's lymphoma cell lines. They expressed low densities of surface mu chains, without detectable cytoplasmic or surface light chains. Three of them were infected with the Epstein Barr virus (EBV). These c mu+ HMCLs bore most of the B-cell antigens except CD23. They expressed the CALLA antigen (CD10) and lacked the plasma-cell antigen PCA1. In contrast, LCLs expressed surface light chains, high densities of CD23, low densities of PCA1 antigen, and no CD10 antigen. The c mu- HMCLs had a plasma-cell phenotype, lacking most of the B-cell antigens and expressing high densities of PCA1 antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Pixantrone demonstrates significant in vitro activity against multiple myeloma and plasma cell leukemia

2019 ◽  
Vol 98 (11) ◽  
pp. 2569-2578
Author(s):  
Ella Willenbacher ◽  
Karin Jöhrer ◽  
Wolfgang Willenbacher ◽  
Brigitte Flögel ◽  
Richard Greil ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Myeloma Cell ◽  
Plasma Cell Leukemia ◽  
Phase Iii ◽  
In Vivo Model ◽  
Cell Leukemia ◽  
Cam Assay

Abstract Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin’s lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).

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 THE BONE MARROW ON STERNAL ASPIRATION IN MULTIPLE MYELOMA

Blood ◽  
1948 ◽  
Vol 3 (9) ◽  
pp. 987-1018 ◽  
Author(s):  
EDWIN D. BAYRD
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Multinucleated Cells ◽  
Cytoplasmic Bodies ◽  
Plasma Cell Type ◽  
Well Differentiated ◽  
Diagnostic Pitfalls

Abstract Generalizing, it can be said that the pathologic cells seen in smears of the bone marrow in multiple myeloma resemble the plasma cell and vary from the very anaplastic and immature cell to the well-differentiated and almost characteristic plasma cell. The feature which the "myeloma" cell shares with the plasma cell is the abundant, granular, basophilic cytoplasm which tends to be fragile and undergo the same degenerative changes in each; namely, the formation of Russell bodies and vacuolization. Fairly frequently a perinuclear clear area or Hof is present and the nucleus tends to be eccentrically placed. Cytoplasmic extensions or pseudopodia may also be seen in either case, but they occur more often and more dramatically in instances of multiple myeloma. Multinucleated cells are commonly seen. In addition, myeloma-plasma cells will often have a large clear nucleolus and a leptochromatic nucleus and will exhibit a tendency to the formation of isolated areas of condensed chromatin. Cytoplasmic extrusions, free cytoplasmic bodies, occasionally complete with Russell bodies and vacuoles are almost universally present. All cases were of the plasma cell type; there was no exception. In these cases, the myeloma-plasma cell constituted from 2.5 to 96 per cent of the leukocytic elements present. The opinion was expressed that all so-called types of multiple myeloma are merely variations in differentiation of this same cell. It was noted that anaplasia, hypernucleation and lack of plasma cell predominance in certain cases were diagnostic pitfalls. Additional evidence was adduced to confirm the reticulo-endothelial origin of the myeloma-plasma cell. It was further observed that certain prognostically valuable information could be gleaned from a careful review of the cytologic characteristics in these cases.

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