Haematologica 2003 - Supplements

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Barlogie B, Shaughnessy J, Jr. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood. 2002;99:1745-1757 P1.2 IG TRANSLOCATIONS, CYCLIN D DYSREGULATION, AND OTHER GENETIC EVENTS IN MULTIPLE MYELOMA M. Kuehl 4 , C. Cultraro 4 , A. Dib 4 , A. Gabrea 4 , M. Martelli 4 , L. Brents 4 , A. Zingone 4 , J. Shaughnessy 1 , J. Sawyer 1 , B. Barlogie 1 , R. Fonseca 2 , M. Chesi 3 , P.L. Bergsagel 3 1. University of Arkansas Medical Sciences; 2 Mayo Clinic; 3. Cornell Medical School; 4. Genetics Dept., NCI, Naval Hospital, Bldg 8, Rm 5101, Bethesda, MD 20889-5105 Tel: (301-435-5421, Fax: (301) 496-0047, Email: wmk@helix.nih.gov MM is post-germinal center tumor of bone marrow plasmablasts/plasma cells. Germinal center B cells modify DNA by sequential rounds of somatic hypermutation and antigen selection, and IgH switch recombination. Post-germinal center B cells can generate plasmablasts (PB) that migrate to the bone marrow (BM), where stromal cells enable terminal differentiation into long-lived plasma cells (PC). MM, a low proliferative tumor that corresponds to long-lived PB/PC, often is preceded by a premalignant MGUS tumor, and sometimes progresses to extramedullary MM. Virtually all human MM cell lines (HMCL) come from extramedullary MM, including primary PC leukemia that occurs without apparent intramedullary MM. Ig translocations: frequent and often early events in the pathogenesis of MM. Ig translocations dysregulate oncogenes by juxtaposing them near one of the strong Ig enhancers. Translocations usually involve the IgH locus, whereas the Igλ locus is involved infrequently, and the Igκ locus rarely. The prevalence of IgH translocations appears to be related to the stage of the disease: about 50% in MGUS, 55-70% in intramedullary MM, >80% in extramedullary MM, and more than 90% in HMCL. Primary Ig translocations occur in germinal center B cells, usually a result of errors in IgH switch recombination, or less often somatic hypermutation. Secondary (Ig) translocations occur during tumor progression. Secondary translocations are mediated by different mechanisms than most primary translocations, since B cell specific DNA modification processes are inactive in normal or malignant PB/PC. Features that often distinguish secondary translocations include: breakpoints not within or near IgH switch or V(D)J sequences, complex and unbalanced translocations or insertions, heterogeneity within a tumor, and sometimes lack of involvement of an Ig enhancer. The dysregulation of c-, N-, or L- MYC, which usually occurs as a very late progression event, provides a paradigm for secondary translocations. The increased prevalence of Ig translocations at later stages of disease and in HMCL probably is explained partly by secondary Ig translocations but also by selective progression of tumors with Ig translocations. Different oncogenes for primary and secondary translocations. Four recurrent chromosomal loci (oncogenes) are involved in primary translocations: 11q13 (cyclin D1); 6p21 (cyclin D3); 4p16 (MMSET; FGFR3); 16q23 (c-maf); and these account for IgH translocations in about 40% of tumors. Loci involved in secondary translocations include: 8q24 (c-myc), 2p23 (N-myc), 20q12 (maf B), and 6p25 (MUM-1/IRF-4), but these probably account for IgH translocations in only 5% of tumors. Nonrecurrent loci are involved in IgH translocations in nearly 20% of tumors, but the fraction of primary vs secondary translocations is unclear. Dysregulation of cyclin D1, 2, or 3: a possible early, unifying event in MM. Despite the low proliferative index of MM tumors, microarray expression analyses indicate that most tumors express one of the cyclin D genes at a level that is similar to proliferating PB, and distinctly higher than quiescent PC. The four recurrent primary translocations appear to lead directly (11q13 - cyclin D1 or 6p21 - cyclin D3), or indirectly (4p16 and 16q23 - cyclin D2) to cyclin D dysregulation. Another 20% of MM tumors express cyclin D2, the major cyclin D gene expressed by normal PB. Remarkably, however, despite the lack of expression of cyclin D1 in normal hematopoietic cells, about one third of MM tumors express substantial levels of cyclin D1 in the absence of a t(11;14) translocation; the mechanism responsible for cyclin D1 expression is obscure, but it is notable that this group of tumors (that we call D1 lo) is represented rarely, if ever, by HMCL. Perhaps, cyclin D1 expression requires a continued interaction of the MM tumor cell and BM stromal cells. Other oncogenic events in MM. Numeric (and possibly structural) karyotypic abnormalities, including monosomy of chromosome 13 or deletion of 13q14, are often present in MGUS, but the timing and molecular consequences of these abnormalities is unclear. Activating mutations of K- or N-RAS [or FGFR3 in tumors with t(4;14)] are absent or rare in MGUS, but present in 40% of early MM, and perhaps 50% of advanced MM; this may represent a marker if not a cause of progression from MGUS to MM. Dysregulation of c-MYC, and mutations or mono-allelic deletion of p53 appear to occur as very late progression events. Presumably telomerase or the ALT pathway is activated during tumorigeneis, but it is uncertain how or when this occurs. Disruption of the Rb pathway occurs in most human tumors; but even though dysregulation of cyclin D appears to be a universal early event in MM, inactivation of RB or INK4 cyclin dependent kinase inhibitors (p16INK4a and p18INK4c) can occur during tumor progression and further disrupt the RB pathway. P1.3 THE MYELOMA HIERARCHY: HETEROGENEITY WITHIN THE MYELOMA CLONE Linda M. Pilarski, Tony Reiman, Andrew R. Belch Department of Oncology, University of Alberta and Cross Cancer Institute Early stage members of the multiple myeloma (MM) clone contribute to disease progression: A variety of evidence suggests that MM represents a hierarchy of monoclonal B lineage cells in the blood and BM that includes late stage B cells and plasma cells, pre-B-like cells and sIgM + pre-switch B cells. Others have described circulating cells expressing the MM idiotype, and circulating cells expressing the unique clonotypic IgH VDJ are readily detectable in blood. We have shown that MM includes circulating B cells that persist despite chemotherapy and may mediate relapse. Even though MM plasma cells are often severely depleted in response to therapy, residual disease and bone lesions usually persist, suggesting a failure of therapy to restore normal bone remodeling and the involvement of clinically cryptic components of the MM clone. The heterogeneity seen among ex-vivo clonotypic B and plasma cells suggests an in vivo hierarchy of sequentially related differentiation stages. These early stage members of the MM clone are morphologically cryptic in that their physical appearance and phenotypic profiles are largely normal, preventing their identification using as “morphologically abnormal” cells. Only their expression of the S16
clonotypic IgH VDJ signature confirms their relationship within the malignant clone. Our observations imply that circulating, early stage components of the MM clone are clinically important. 1) Circulating clonotypic MM B cells are able to produce and secrete IL-6 ex vivo (1), and strongly express CD31, the ligand for CD38, predicted to facilitate paracrine interactions with the ostoclast lineage and to exacerbate bone resorption in MM. Clonotypic MM B cells express surface IL-6 receptor α subunit, a prerequisite for autocrine and/or paracrine stimulatory loops. 2) Xenografted early stage MM B cells give rise to lytic bone disease, clonotypic progeny and are self-renewing in murine BM. 3) Hematopoietic progenitor fractions of G-CSF mobilized blood, comparable to those used for autotransplants and shown to include clonotypic MM components, and MM B cells, engraft the myeloma clone and generate bone lesions in xenografted mice. 4) Chemotherapy-resistant, pre-switch progenitors of the MM clone correlate with advanced disease at diagnosis and with significantly reduced survival (2). Direct evidence that circulating, pre-switch progenitors have a strong influence on MM progression comes from longitudinal analysis showing a strong correlation between persistent, and thus drug-resistant, pre-switch MM cells and reduced survival (p
Page 1 and 2: Focussed Symposia Arsenic trioxide
Page 3 and 4: assess whether such a program will
Page 5 and 6: The overall response rate was noted
Page 7 and 8: Figure 5A Table 1: VEL + THAL for R
Page 9 and 10: naturally occurring OPG. Present tr
Page 11 and 12: 0.505). Finally, the multiple event
Page 13 and 14: CLINICOPATHOLOGICAL DEFINITION OF W
Page 15: Plenary Sessions 1. Development of
Page 19 and 20: can be considered as two entities,
Page 21 and 22: immunofluorescence staining for DKK
Page 23 and 24: P2.3 DEVELOPMENT OF A MULTIPLE MYEL
Page 25 and 26: P2.5 MOLECULAR CYTOGENETICS OF MYEL
Page 27 and 28: clear that the biggest challenge fo
Page 29 and 30: esponse and have demonstrated that
Page 31 and 32: variable region of the idiotypic im
Page 33 and 34: 4. From MGUS to symptomatic MM Fig.
Page 35 and 36: (MRI); some have claimed that level
Page 37 and 38: P4.5 CYTOKINES IN MGUS: THERAPEUTIC
Page 39 and 40: preventing phosphorylation of p70S6
Page 41 and 42: transducing component of the interl
Page 43 and 44: survive initial drug exposure and a
Page 45 and 46: quiescent counterpart, the human um
Page 47 and 48: transcriptional activity of NF-êB;
Page 49 and 50: manifestations and anomalous protei
Page 51 and 52: P7.4 ROLE OF SERUM FREE LIGHT CHAIN
Page 53 and 54: P7.6 IMMUNOPHENOTYPIC INVESTIGATION
Page 55 and 56: presumably through the circulation,
Page 57 and 58: 9. Chemotherapy, maintenance treatm
Page 59 and 60: stratified according to their antim
Page 61 and 62: explore higher doses of zoledronic
Page 63 and 64: initial therapy. However, the role
Page 65 and 66: 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.
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MHC molecules, in effectively prese
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mice demonstrate that class II-spec
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detected in 293 and NIH3T3 cells. S
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hypothesis that (1) CCND1 and FGFR3
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patient samples. In addition, the p
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016 NEUTRAL ENDOPEPTIDASE (CD10) KN
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2. Genetic heterogeneity in MM: imp
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evidence from two t(11;14) cases wh
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immunoglobulin heavy chain (IgH) lo
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034 Instability of Pericentromeric
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clusters were found, the first was
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MGUS but most likely not crucial fo
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Objective: To compare the impact on
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4 patients had MMSET/IgH but did no
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and clonal PC from MGUS, MM and PCL
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059 VEGF receptor expresion in Mult
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two HLA-A2+ myeloma patients with C
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molecules expressed on the surface
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Recognition of these antigens appea
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Diagnosis requires a single area of
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081 Incidence of solid tumors in co
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Growth Factor (VEGF), Hepatocyte Gr
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PC-AI levels of MGUS and SMM patien
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093 The predominant pathway of tran
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was associated with I.V. line, whil
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103 Vascular amyloidosis induces se
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5. Signal transduction pathways and
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integrin in IGF-1-triggered MM cell
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118 IL-6- Induced Phosphorylation o
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123 THE IGF/IGF-1R SYSTEM IS A MAJO
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human myeloma cell line (HMCL) to a
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ligation or dexamethasone (Georgii-
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6. Role of microenvironment 6.1 Cel
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141 Human myeloma cells adhere to f
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145 STUDY OF BONE MARROW ANGIOGENES
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patients, the growth of primary mye
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tibia (con=49.1±0.7mg/cm2 vs 5T2=4
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157 The Nitrogen-Containing Bisphos
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7. New prognostic criteria for clas
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atio of >3. This system has subdivi
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Patient 1 (IgG/κ);IgG - 16.5 days,
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176 Pro-inflammatory and angiogenic
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180 Clinical study on the bone lesi
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7.2 Imaging studies 185 99mTc-MIBI
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189 Factors Predicting Occult Spina
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vivo detected resonances was invest
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Support Unit (CTSU) with flexibilit
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(β2m) & C reactive protein (CRP).
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plasmids carrying the clonotypic in
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newly diagnosed multiple myeloma as
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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
Page 289 and 290:
Morra E 249 280 359 Morris CM 226 M
Page 291 and 292:
Siegel D 70 115 250 Sierra J 304 30
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