Haematologica 2003 - Supplements

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105 Development of ATLL during follow up of Multiple Myeloma with previous positive sorology for Human T Cell Leukemia virus. Martinez, G.A ; Kondo, A. ; Fonseca, G.; Pereira, J.; Beitler, B.; Dorlhiac-Llacer,P.E.; Chamone, D. Department of Hematology University of São Paulo, Hospital das Clínicas, São Paulo, Brazil. Fundação Pró-Sangue Hemocentro de S. Paulo. We report a case of ATLL 23 months after the diagnosis of Multiple Myeloma. Case Report: A 73 years old black woman with bronchopneumonia and anaemia was admitted for investigation. Laboratory data showed: Hb: 6,5g/dl; Serum eletroforesis: monoclonal globulin: 5,43g/dl. Imunoeletrophoresis: IgA kappa. Renal function and serum calcium were both normal. The bone marrow showed increased number (40%) of pathological plasma cells (PC). A bone survey revealed colapse of T7 and L3 and osteopenia. A diagnosis of MM, stage IIIA, was made. At this time the sorology for HTLV was positive: WESTERN BLOT GD21(+); P19 (+); P24 (+). She was begun on melphalan 10 mg/m2 plus dexamethasone (DXM) 20mg vo (D1-D4). The controls 18 months after diagnosis showed: Hb10,7 g/dl; Leukocytes 4100/mm3; neutrophils: 2100/mm3; limphocytes: 1300/mm3; Platelets: 276000/mm3, stable paraprotein 2,68g/dl and bone marrow aspirate showing 29,5% PC and 3% lymphocytes. One month after the last avaliation, she was admitted to the hospital in coma. Investigations showed anaemia (Hb: 9,2 g/dl), leukocytosis: 199.400/mm3 with lymphocytosis (76%) and hypercalcemia: 7,6mg/dl (normal: 4,8- 5,28mg/dl), monoclonal protein 2,18g/dl and high serum lactate dehydrogenase level: 2.174 (normal
5. Signal transduction pathways and cytokine networks 5.1 Surface reception. 108 ATYPICAL RECEPTOR INTERACTIONS IN MYELOMA CELLS: USE OF RNA INTERFERENCE (RNAi) TO INVESTIGATE FUNCTIONAL SIGNIFICANCE Denise K. Walters and Diane F. Jelinek Dept. of Immunol. and the Tumor Biology Graduate Program, Mayo Graduate School, Mayo Clinic, Rochester, MN, USA, 55905. Our laboratory has had a long-standing interest in the growth regulation of myeloma cells. Furthermore, we have had a particular interest in multiple myeloma (MM) cell responsiveness to interferon-alpha (IFN-α because of its ability to modulate myeloma cell growth in a variable manner. Thus, IFN-α typically results in growth inhibition of myeloma cells, however some MM cells, such as the KAS-6/1 MM cell line, display an atypical growth response. Moreover, during the course of other studies, we serendipitously and unexpectedly discovered that the IFN-α growth responsive KAS-6/1 MM cell line expresses ErbB3, whereas MM cell lines that are growth arrested by IFN- do not. In this regard, there is a growing awareness of the complications introduced by unexpected receptor interactions that result in synergistic down-stream cellular effects, e.g., enhanced growth or resistance to apoptosis of cancer cells. We hypothesized, therefore, that ErbB3 expression may play a role in the atypical IFN-KAS-6/1 response. Indeed, we were initially able to demonstrate that IFN-α stimulation resulted not only in the activation of the IFN-α receptor, but also in the transactivation of ErbB3, as revealed by tyrosine phosphorylation. To address the significance of these observations, we employed two strategies. First, we transfected ErbB3 negative DP-6 MM cells with ErbB3 and analyzed whether IFN-α stimulation could transactivate ectopically expressed ErbB3. Although IFN-α transactivated ErbB3 in the DP-6 transfectants, it did not confer growth responsiveness to IFN-α. Second, we wished to use RNA inhibition (RNAi) to assess the functional significance of atypical expression of ErbB3 in the KAS-6/1 cells. RNA interference (RNAi) is a recently discovered natural response to double-stranded RNA (dsRNA) that can result in sequence specific gene silencing. In ancillary studies aimed at adapting this methodology to myeloma cells, we demonstrated the striking dependence of dsRNA-mediated gene silencing in some cells on the methods of dsRNA transfection. Thus, we were able to optimize the inhibitory effects of ErbB3 siRNA in the KAS-6/1 cells by utilizing electroporation, rather than conventional transfection agents, to transfect the cells. Using Western blot analysis, we were able to demonstrate that ErbB3 siRNA treatment resulted in the loss of this receptor from the KAS-6/1 cells. Of great interest, silencing ErbB3 expression in KAS-6/1 cells decreased the overall growth response to both IFN-α and IL-6. Taken together these two lines of investigation suggest that ErbB3 expression alone does not uniquely confer IFN-α growth responsiveness but instead, may amplify proliferation rates in MM cells that have acquired atypical expression of this receptor. In conclusion, we believe that novel receptor interactions have the potential to allow dysregulated tumor cell function. In this regard, atypical expression of ErbB3 in multiple myeloma may provide a mechanism whereby the tumor cell is afforded with either an ability to grow or to survive. We are currently investigating this possibility, along with analyzing primary myeloma cells for ErbB3 expression. 109 DOWN-MODULATION OF ERK PROTEIN KINASE ACTIVITY SUPPRESSES HUMAN MYELOMA CELL PROLIFERATION AND MYELOMA-INDUCED ANGIOGENESIS BY VEGF INHIBITION Nicola Giuliani2, Paolo Lunghi1, Francesca Morandi, Magda Hojden2, Sabrina Bonomini2, Simona Colla2, Giovanni Roti2 , Regis Bataille3, Vittorio Rizzoli2, Antonio Bonati1 1Insitute of Medical Pathology and 2Hemaology, University of Parma, Italy, 3INSERM U463, Nantes, France. The mitogen-activated protein (MAP) cascade leading to the activation of ERK (Extracellular signal-regulated kinase) is critical for regulating myeloma cell growth, however the relationships of ERK1/2 protein kinases activity with vascular endothelial growth factor (VEGF) production and the effects of their down-modulation in myeloma cells are not completely investigated. In order to elucidate this issue we first studied the expression and the activation of ERK1/2 protein kinases in RPMI-8226, XG6, U266 and OPM-2 human myeloma cell lines (HMCL) (5x106) growing in 5ml of complete RPMI medium with or without IL-6 (20ng/ml). By immunoenzymatic MAP kinase assay using Elk1 as substrate (Elk1-p) or dualphosphorylation-ERK1/2 specific antisera (p-ERK1/2) we found that steady-state levels of phosphorylated ERK 1/2 (p-ERK) were stronger in U266 than RPMI, and XG6. The total amounts of ERK1 and ERK2 proteins were comparable in U266, XG6 and OPM-2 whereas in RPMI the expression of ERK1 was significantly higher. Basal VEGF secretion, detected by ELISA was similar in OPM-2 (Mean±SD: 835±10 pg/ml), XG-6 (668±15 pg/ml), U266 (739±12 pg/ml) and higher in RPMI-8226 (1381.6± 20pg/ml). IL-6 stimulation significantly increased ERK1/2 activity and VEGF secretion in XG-6, U266, RPMI-8226. Therefore, we used the specific inhibitor of MEK, PD98059, in order to down-modulate activated ERK1/2 (p-ERK1/2). The treatment for 2 hours of myeloma cells with 40mM of MEK-1 inhibitor PD98059 produced a reduction of p-ERK1/2 levels of more than 80% and prevented the increase of p-ERK1/2 induced by IL-6 treatment. PD98059 induced a significant inhibition of HMCL proliferation (-33±5%) and blunted the stimulatory effect induced by IL-6. A more potent inhibition on HMCL proliferation was observed with the ERK inhibitor PD184352 at 2mM (-70%±4%). PD184352 but not PD98059 induced HMCL apoptosis in combination with anti CD95 mAb or Arsenic Trioxide 2m. A significant dose and time dependent inhibition on basal VEGF secretion by HMCL was induced by PD98059 treatment, more evident in RPMI-8226 (771±12 vs 1350±18 pg/ml, -43%; p
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Focussed Symposia Arsenic trioxide
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assess whether such a program will
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The overall response rate was noted
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Figure 5A Table 1: VEL + THAL for R
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naturally occurring OPG. Present tr
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0.505). Finally, the multiple event
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CLINICOPATHOLOGICAL DEFINITION OF W
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Plenary Sessions 1. Development of
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clonotypic IgH VDJ signature confir
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can be considered as two entities,
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immunofluorescence staining for DKK
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P2.3 DEVELOPMENT OF A MULTIPLE MYEL
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P2.5 MOLECULAR CYTOGENETICS OF MYEL
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clear that the biggest challenge fo
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esponse and have demonstrated that
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variable region of the idiotypic im
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4. From MGUS to symptomatic MM Fig.
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(MRI); some have claimed that level
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P4.5 CYTOKINES IN MGUS: THERAPEUTIC
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preventing phosphorylation of p70S6
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transducing component of the interl
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survive initial drug exposure and a
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quiescent counterpart, the human um
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transcriptional activity of NF-êB;
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manifestations and anomalous protei
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P7.4 ROLE OF SERUM FREE LIGHT CHAIN
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P7.6 IMMUNOPHENOTYPIC INVESTIGATION
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presumably through the circulation,
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9. Chemotherapy, maintenance treatm
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stratified according to their antim
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explore higher doses of zoledronic
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initial therapy. However, the role
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P10.2.2 SINGLE VERSUS TANDEM HIGH D
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With a median follow-up of 38 month
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cells could be harvested following
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11. What is the role of allogeneic
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found that 75% of patients who were
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patients with responsive disease 3
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9. Giralt S, Estey E, Albitar M, et
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Badros A, Barlogie B, Siegel E, et
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Figure 3b. Event-free Survival 4-Ye
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improve patient outcome in MM. Impo
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myeloma and in 40% of previously un
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degrade OPG in the same way as myel
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P12.2.5 MONOCLONAL ANTIBODY THERAPY
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myeloma. Blood 2001; 98:210-216. 6.
Page 93 and 94: MHC molecules, in effectively prese
Page 95 and 96: mice demonstrate that class II-spec
Page 97 and 98: detected in 293 and NIH3T3 cells. S
Page 99 and 100: hypothesis that (1) CCND1 and FGFR3
Page 101 and 102: patient samples. In addition, the p
Page 103 and 104: 016 NEUTRAL ENDOPEPTIDASE (CD10) KN
Page 105 and 106: 2. Genetic heterogeneity in MM: imp
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Page 109 and 110: immunoglobulin heavy chain (IgH) lo
Page 111 and 112: 034 Instability of Pericentromeric
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Page 115 and 116: MGUS but most likely not crucial fo
Page 117 and 118: Objective: To compare the impact on
Page 119 and 120: 4 patients had MMSET/IgH but did no
Page 121 and 122: and clonal PC from MGUS, MM and PCL
Page 123 and 124: 059 VEGF receptor expresion in Mult
Page 125 and 126: two HLA-A2+ myeloma patients with C
Page 127 and 128: molecules expressed on the surface
Page 129 and 130: Recognition of these antigens appea
Page 131 and 132: Diagnosis requires a single area of
Page 133 and 134: 081 Incidence of solid tumors in co
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Page 137 and 138: PC-AI levels of MGUS and SMM patien
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Page 141 and 142: was associated with I.V. line, whil
Page 143: 103 Vascular amyloidosis induces se
Page 147 and 148: integrin in IGF-1-triggered MM cell
Page 149 and 150: 118 IL-6- Induced Phosphorylation o
Page 151 and 152: 123 THE IGF/IGF-1R SYSTEM IS A MAJO
Page 153 and 154: human myeloma cell line (HMCL) to a
Page 155 and 156: ligation or dexamethasone (Georgii-
Page 157 and 158: 6. Role of microenvironment 6.1 Cel
Page 159 and 160: 141 Human myeloma cells adhere to f
Page 161 and 162: 145 STUDY OF BONE MARROW ANGIOGENES
Page 163 and 164: patients, the growth of primary mye
Page 165 and 166: tibia (con=49.1±0.7mg/cm2 vs 5T2=4
Page 167 and 168: 157 The Nitrogen-Containing Bisphos
Page 169 and 170: 7. New prognostic criteria for clas
Page 171 and 172: atio of >3. This system has subdivi
Page 173 and 174: Patient 1 (IgG/κ);IgG - 16.5 days,
Page 175 and 176: 176 Pro-inflammatory and angiogenic
Page 177 and 178: 180 Clinical study on the bone lesi
Page 179 and 180: 7.2 Imaging studies 185 99mTc-MIBI
Page 181 and 182: 189 Factors Predicting Occult Spina
Page 183 and 184: vivo detected resonances was invest
Page 185 and 186: Support Unit (CTSU) with flexibilit
Page 187 and 188: (β2m) & C reactive protein (CRP).
Page 189 and 190: plasmids carrying the clonotypic in
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Page 193 and 194: 216 Transgenic expression of Myc an
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221 Prolonged survival in the 5T2MM
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9. Chemotherapy, maintenance, treat
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229 EFFECTIVENESS OF STANDARD CHEMO
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234 Melphalan and Dexamethasone- Is
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Methods. We investigated the VECD p
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9.2 Renal complications. 243 MERIT
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cost of SRE-related care was $10,24
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those with Hb >13 g/dL. Analysis of
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sustained response, lasting from 52
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proportion of bone abnormality. IgD
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disease. The lack of response to in
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yielding a median of 3x106/kg CD34
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patients(pts) aged ≥60 yrs. We co
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PBSC mobilizing regimen utilizing C
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their leukocytes and platelets. No
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25 Gy to marrow. The tracer dose wa
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non-CR after the first transplant a
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296 PERIPHERAL BLOOD STEM CELL TRAN
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References Effect of dose-intensive
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with cyclosporine A and methotrexat
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11.Role of novel therapies targetin
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312 Thalidomide as Rescue of Relaps
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patients, light chain in 1 patients
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platelets of 207 (76-402), B2M of 3
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325 Low Dose Thalidomide plus Dexam
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in 5 pts (11%), M protein decreased
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time from diagnosis was 3.7 years a
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339 Thalidomide, Clarithromycin and
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344 COMBINATION OF THALIDOMIDE, DEX
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experienced early death during the
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untreated patients with high tumor
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357 Thalidomide protects endothelia
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362 EOSINOPHILIA IS A VERY COMMON F
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11.5 CC 4047, PS 341 and arsenic tr
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without chromosome 13. Mean IC50 fo
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myeloma patients. Phase I data indi
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11.6 Other drugs 380 EFFECT OF STI5
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significant inhibition of cell prol
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which acts to prevent the synthesis
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of B and its metabolites, however,
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and 10 months after start of therap
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terminal kinase (JNK) pathway which
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lymphocytes was tested by Ellispot.
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411 Dendritic Cell-Based Idiotype V
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Author Index Abe M 74 160 Abelman W
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De La Serna J 291 De Laurenzi A P11
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Hull DR 338 Hullen C P10.2.1 Humes
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Morra E 249 280 359 Morris CM 226 M
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Siegel D 70 115 250 Sierra J 304 30
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