H e m a t o lo g y E d u c a t io n - European Hematology Association

More documents

Recommendations

Info

A. Vacca 1 D. Ribatti 2 1 Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Italy; 2 Department of Human Anatomy and Histology, University of Bari Medical School, Italy Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:273-279 Multiple myeloma Angiogenesis and antiangiogenesis in patients with multiple myeloma First evidence of an increased angiogenesis in bone marrow of multiple myeloma patients In 1994, Vacca and colleagues demonstrated for the first time that bone marrow microvascular density was significantly increased in multiple myeloma (MM) compared with monoclonal gammopathy of undetermined significance (MGUS), and in active versus nonactive MM. The authors first hypothesized that progression from MGUS parallels an increase in bone marrow microvascular density. 1 As progression from in situ to invasive and metastatic solid tumors is accompanied and enhanced by the switch from the prevascular to the vascular phase, these findings suggest that active MM represent the ‘vascular phase’ of plasma cell tumors, and nonactive MM and MGUS their ‘prevascular phase’. Subsequent studies by others confirmed the observation of increased angiogenesis in active MM compared to MGUS or healthy individuals. 2–5 Cytokines involved in the angiogenic switch The mechanisms of induction of the vascular phase are the subject of current investigation. 6 Several studies show overexpression and secretion of the vascular endothelial growth factor (VEGF) by the clonal plasma cells. VEGF stimulates proliferation and chemotaxis in both endothelial cells via VEGF receptor-2 (VEGFR-2) and bone marrow stromal cells (BMSCs) via VEGFR-1. VEGFRs are rapidly phosphorylated by the interaction with VEGF, and signal via extracellular signal-related kinase-2 (ERK-2). 7 Plasma cell-derived VEGF also stimulates A B S T R A C T Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and has prognostic potential. The pathophysiology of MM-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment in stromal cells. Cytokines promote plasma cell growth, survival and migration, and angiogenesis. It has been demonstrated that bone marrow macrophages and mast cells are closely involved in vasculogenic mimicry, thus contributing together with circulating endothelial cells and endothelial precursor cells (EPCs) to the MM neovascularization. An improved understanding of the importance of angiogenesis-related signaling in MM has allowed for the rational use of antiangiogenic therapies in this tumor. interleukin-6 (IL-6) and VEGF secretion in BMSCs, whereas BMSCs-derived IL-6 promotes proliferation, survival, and VEGF production in plasma cells. 8 Fibroblast growth factor-2 (FGF-2) is also secreted by MM cells. 9 Levels of FGF-2 are significantly higher in the plasma cell lysates of patients with active MM compared with nonactive MM and MGUS patients. Inhibition of FGF-2 by an anti-FGF-2 antibody suppressed the angiogenic potential of plasma cells from patients with active MM. 9 Moreover, FGF-2 triggers paracrine myeloma-BMSCs interactions in an IL-6/FGF-2 paracrine loop. 10 Syndecan-1 (CD138), a low affinity receptor of FGF-2, is also expressed by MM cells. 11 Hepatocyte growth factor (HGF) and its receptors c-Met and angiopoietin-1 (Ang-1) have been described as additional angiogenic factors in MM. 12–14 HGF has been identified in human MM cell lines12 and in freshly isolated MM cells. 13 Serum levels of this factor are high in approximately 40% of patients at diagnosis and decline to normal levels with response to induction therapy. There is no decline if the therapy is ineffective, and the levels become high again upon release. 15 Giuliani et al. found that Ang-1 expression is up-regulated in MM cell lines or in patients’ plasma cells, and that the Ang-1 expression in the patients’ samples correlated with bone marrow microvascular density. 14 Furthermore, they demonstrated that the Ang-1 receptor Tie-2 is up-regulated in the bone marrow endothelial cells in the presence of MM cells, and that an anti-Tie2 antibody blocked the in vitro angiogenic activity of MM cells. Insulin like growth factor-1 (IGF-1) plays a role in the angiogenic process by stimulating MM cells to secrete VEGF. 16 Plasma IL-8 is increased in MM. 17 Osteopontin (OPN) was Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 273 |
16 th Congress of the European Hematology Association found to contribute to angiogenesis in MM, 18 and OPN expression correlated with bone marrow microvascular density. 19 Matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) secretion is increased in patients with active versus nonactive MM or MGUS. 9 A number of MM cell lines and freshly isolated bone marrow plasma cells produce MMP-9, although correlation with disease activity has not been assessed. 20 MMP secretion of MM cells is triggered by BMSCs or endothelial cells. 21 We have demonstrated that platelet-derived growth factor (PDGF)-receptor beta (PDGFRβ) and pp60-Src as constitutively activated tyrosine kinases (TKs) are expressed in plasma cells of MM patients. 22 The PDGF- BB/PDGFRβ axis promoted MM tumor growth by activating ERK-1/2 and AKT, and this activity was selectively induced by VEGF. Airoldi et al. demonstrated that IL-12 receptor B2 (IL- 12Rβ2) was expressed in primary MM cells but downregulated compared with normal plasma cells. 23 IL-12 reduced the pro-angiogenic activity of primary MM cells in vitro and decreased significantly the tumorigenicity of NCI-H929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. Hose et al. have reported that normal bone marrow plasma cells express several angiogenic genes, including VEGF-A, IGF-1, and adrenomedullin (ADM), and their culture supernatants significantly induce in vitro angiogenesis. 24 MM plasma cells show a pattern of aberrant expression of several angiogenic factors, and culture supernatants of primary MM cells and human cell lines induce in vitro angiogenesis. However, none of these factors was expressed in any of the MM patients’ samples, and no correlation with microvascular density could be found. The role of the bone marrow microenvironment The MM microenvironment is formed by clonal plasma cells, extracellular matrix proteins, and BMSCs, which are intimately involved in all biological stages of intramedullary growth. 25 Reciprocal positive and negative interactions between plasma cells and BMSCs are mediated by an array of cytokines, receptors, and adhesion molecules. Interactions between these components give proliferation, migration, and survival of plasma cells, as well as their drug resistance. 26–28 Plasma cells secrete several cytokines, such as tumor necrosis factor alpha (TNF-α), 29 transforming growth factor beta (TGF-β), VEGF, FGF-2, 9 HGF, 12,13 Ang-1, 14 and MMPs, 9 into their microenvironment. Moreover, binding of plasma cells to BMSCs triggers transcription and secretion of cytokines by the latter, such as IL-6, 8 IGF-1, 30 VEGF, 31 and CXCL12/stromal cell derived factor-1α (SDF-1α) 32 that mediate cell growth (IL-6, IGF-1, VEGF), survival (IL-6, IGF-1), drug resistance (IL-6, IGF-1, VEGF), migration (IGF-1, VEGF, MMPs, SDF-1α), and angiogenesis (VEGF). The role of bone marrow endothelial cells Vacca et al. demonstrated that the endothelial cells of MM bone marrow (MMECs) are characterized by an enhanced expression of specific angiogenic factors/receptors, such as VEGF/VEGFR-2, FGF-2/FGF- 2R-2, and Ang-2/Tie-2, and by an increased in vitro and in vivo angiogenic activity. 33 These endothelial cells express more mRNA and secrete larger amounts of the CXC-chemokines CXCL8/IL-8, CXCL11/interferon-inducible T-cell alpha chemoattractant (I-TAC), CXCL12/SDF-1α, and CCL2/monocyte chemotactic protein-1 (MCP-1) than human umbilical vein endothelial cells (HUVECs). Since paired plasma cells express cognate receptors to a variable extent, paracrine loops between MMECs and plasma cells involving CXC-chemokines and their receptors may be operative in patients and mediate plasma cell proliferation and homing. 32 We have demonstrated that pp60c-Src is a key signaling effector of the VEGF loop required for MMECs’ survival, migration and angiogenesis, and assessed the antiangiogenic activity of dasatinib, a novel orally bioactive PDGFRβ/Src TK-inhibitor that significantly delayed MM angiogenesis in vivo. 22 We have carried out a comparative gene expression profiling of MMECs versus MGUS endothelial cells (MGECs) with an Affymetrix assay. 34 Twenty-two genes were found differentially expressed (14 downregulated and 8 up-regulated) in MMECs versus MGECs. Deregulated genes were mostly involved in extracellular matrix formation and bone remodeling, cell adhesion, chemotaxis, angiogenesis, resistance to apoptosis, and cell-cycle regulation. Validation was focused on DIRAS3, SERPINF1, SRPX, BNIP3, IER3, and SEPW1 genes, which were not previously found to be functionally correlated to the overangiogenic phenotype of MMECs. Small interfering RNA for the up-regulated genes BNIP3, IER3, and SEPW1 affected critical endothelial cell functions mediating this overangiogenic phenotype, for example, proliferation, apoptosis, adhesion, and capillary tube formation. The role of circulating endothelial cells and endothelial precursor cells Zhang et al. demonstrated that circulating endothelial cells (CECs) and endothelial precursor cells (EPCs) in peripheral blood were six-fold higher in MM patients than in controls and correlated with serum M protein and β2-microglobulin. 35 Circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation, which were inhibited by thalidomide treatment. Co-expression of VEGFR-2 and CD133 characterized EPCs and VEGFR-2 mRNA elevations correlated with the M protein levels. We have demonstrated that in patients with active MM, plasma cells and stromal cells in the microenvironment recruit hematopoietic stem precursor cells (HSPCs) and induce their differentiation into mature MMECs. 36 In fact, when incubated with VEGF, FGF-2, and IGF, HSPCs differentiate into endothelial-like cells expressing typical endothelial markers, such as FVIII- RA, VEGFR-2, and VE-cadherin, and form capillary-like networks in vitro. 36 Bone marrow MM but not MGUS biopsies revealed HPSCs inside the neovessel wall, suggesting that in the former, HSPCs contribute to the | 274 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
Page 1 and 2:
H e m a t o l o g y E d u c a t i o
Page 3 and 4:
Copyright Information ©2011 by Eur
Page 5 and 6:
Editorial Board Education Book Edit
Page 7 and 8:
Acute lymphoblastic leukemia 1-8 Th
Page 10 and 11:
S. Schnell P. Van Vlierberghe A. Fe
Page 12 and 13:
lineage cells, and in differentiati
Page 14 and 15:
FLT3 mutations The FMS-like tyrosin
Page 16 and 17:
44. Bar-Eli M, Ahuja H, Foti A, Cli
Page 18 and 19:
J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
Page 20 and 21:
treated on the MRC UKALL XII/ECOG29
Page 22 and 23:
asparaginase (PEG), where the Esche
Page 24 and 25:
or higher. It is, however, importan
Page 26 and 27:
25. Bruggemann M, Schrauder A, Raff
Page 28 and 29:
lymphoblastic leukemia: prospective
Page 30 and 31:
such as high white blood cell count
Page 32 and 33:
doxorubicine, there was a trend tow
Page 34 and 35:
of the aging process with respect t
Page 36 and 37:
K.L. Rice 1 M. Buzzai 2 J. Altman 1
Page 38 and 39:
ing FLT3-ITD, wild-type NPM1, or bo
Page 40 and 41:
ciated with gene activation, via th
Page 42 and 43:
leukemia with inv(16) and t(8;21):
Page 44 and 45:
99. Parsons DW, Jones S, Zhang X, e
Page 46 and 47:
abnormalities, some of which are al
Page 48 and 49:
file. 27,31 Thus, the double gene-m
Page 50 and 51:
karyotype represents a distinct gen
Page 52 and 53:
Table 1. Meta-analysis of 23 random
Page 54 and 55:
A recent study by the Center for In
Page 56 and 57:
Patients with HLA-matched related o
Page 58 and 59:
After allogeneic HSCT, an autologou
Page 60 and 61:
A. Bacigalupo Ospedale San Martino,
Page 62 and 63:
Table 2. The effect of HLA mismatch
Page 64 and 65:
References 1. Petersdorf EW, Malkki
Page 66 and 67:
neutrophil and platelet recovery an
Page 68 and 69:
Figure 2. One Year-Overall Survival
Page 70 and 71:
infused on day 21. No serious adver
Page 72 and 73:
W, et al. Effect of graft source on
Page 74 and 75:
TRM was higher for patients who rec
Page 76 and 77:
following a myeloablative preparati
Page 78 and 79:
effect. Surprisingly, none of the p
Page 80 and 81:
nancies. Bone Marrow Transplant. 20
Page 82 and 83:
J.G. Gilles Center for Molecular an
Page 84 and 85:
14C12 was humanized by grafting VH
Page 86 and 87:
Table 1. VWD Classification. VWD Su
Page 88 and 89:
Figure 1. Missense mutations found
Page 90 and 91:
associated with an increased bleedi
Page 92 and 93:
49. Brown SA, Eldridge A, Collins P
Page 94 and 95:
leed. These issues are especially i
Page 96 and 97:
estored function. 43,44 A phase I t
Page 98 and 99:
years’ experience of prophylactic
Page 100 and 101:
J.A. Burger Department of Leukemia,
Page 102 and 103:
chemotaxis, migration across vascul
Page 104 and 105:
Regulatory T cells (T reg), identif
Page 106 and 107:
16. Burger JA, Ghia P, Rosenwald A,
Page 108 and 109:
TE, Nowakowski GS, et al. CD49d exp
Page 110 and 111:
andomized trial demonstrating impro
Page 112 and 113:
Conclusions Chemoimmunotherapy has
Page 114 and 115:
with multiple comorbidities (≥ 2)
Page 116 and 117:
ment was finished in all 100 patien
Page 118 and 119:
Table 2. Treatment recommendation f
Page 120 and 121:
34. Ferrajoli A. The combination of
Page 122 and 123:
to be the source of additional gene
Page 124 and 125:
potential to prevent LSCs from acce
Page 126 and 127:
ABL1 confirms that eradication of d
Page 128 and 129:
65. Fiskus W, Pranpat M, Balasis M,
Page 130 and 131:
alive after 10 years. 11 Hence, CCy
Page 132 and 133:
each arm). A minimal change in myel
Page 134 and 135:
Any discussion about the definition
Page 136 and 137:
H. Kantarjian J. Cortes Leukemia De
Page 138 and 139:
59%; the CCyR rate was 44%. Among p
Page 140 and 141:
ern era of BCR-ABL1 tyrosine kinase
Page 142 and 143:
the hematopoietic system, 10 nor in
Page 144 and 145:
over the period of 6 weeks, demonst
Page 146 and 147:
Data on clonal changes in the blood
Page 148 and 149:
2006 Feb 1;107(3):924-30. 41. Liang
Page 150 and 151:
demonstrated that changes in osteob
Page 152 and 153:
“Mafia” transgenic mice in whic
Page 154 and 155:
68. Coetzee T, Fujita N, Dupree J,
Page 156 and 157:
ization. In WASP deficiency, lympho
Page 158 and 159:
Currently the epistatic relationshi
Page 160 and 161:
R. Küppers Institute of Cell Biolo
Page 162 and 163:
Figure 1. TNFAIP3 mutation in HL ce
Page 164 and 165:
Figure 2. HRS cells and their precu
Page 166 and 167:
Hansmann ML, et al. Detection of cl
Page 168 and 169:
fying patients for whom different a
Page 170 and 171:
prognosis HL, whilst those with res
Page 172 and 173:
12. Noordijk EM, Carde P, Dupouy N,
Page 174 and 175:
A. Sureda Consultant in Haematology
Page 176 and 177:
Figure 1. Long-term outcome of pati
Page 178 and 179:
from a MRD and 18 from MUDs. All pa
Page 180 and 181:
Parker PM, Stein AS, et al. High-do
Page 182 and 183:
R. Stasi Department of Haematology,
Page 184 and 185:
common variants in the regulatory r
Page 186 and 187:
against the TPO receptor (cMpl). 61
Page 188 and 189:
W.B. Mitchell A.A. Miller J.B. Buss
Page 190 and 191:
platelet counts and/or bleeding. Th
Page 192 and 193:
Mpl. Cell. 1994;77(7):1117-24. 6. d
Page 194 and 195:
ity and mortality associated with t
Page 196 and 197:
to azathioprine, and is particularl
Page 198 and 199:
stemming from antibodies against PE
Page 200 and 201:
L. Pasqualucci Institute for Cancer
Page 202 and 203:
cation of molecularly distinct subg
Page 204 and 205:
of cases) 46 and amplifications of
Page 206 and 207:
gene alterations in B cell lymphoma
Page 208 and 209:
W. Wilson National Cancer Institute
Page 210 and 211:
clear distinction among the lymphom
Page 212 and 213:
Treatment strategies in germinal ce
Page 214 and 215:
in ABC DLBCL (Hernandez et al., 201
Page 216 and 217:
DLBCL that mostly occurs in young p
Page 218 and 219:
phoma. J Clin Oncol. 2005;23:5347-5
Page 220 and 221:
Table 1. Diffuse Large B cell Lymph
Page 222 and 223:
sion/relapse are similar to those i
Page 224 and 225:
intensive therapy with curative int
Page 226 and 227:
A. Karsan Genome Sciences Centre an
Page 228 and 229:
Balanced translocations In contrast
Page 230 and 231:
some arm 5q have also been implicat
Page 232 and 233: (H3K27) methyltransferase, and is a
Page 234 and 235: 38. Starczynowski DT, Morin R, McPh
Page 236 and 237: G. Garcia-Manero Department of Leuk
Page 238 and 239: trial evaluating different doses an
Page 240 and 241: acid. 62 The second was a large mul
Page 242 and 243: Borthakur G, et al. Cause of death
Page 244 and 245: P. Krishnamurthy 1 G.J. Mufti 1,2 1
Page 246 and 247: etween 1995 and 2005. 11 Five hundr
Page 248 and 249: London, United Kingdom, June 9-12,
Page 250 and 251: attainment of FDC post DLI. Interes
Page 252 and 253: myelodysplastic syndromes is associ
Page 254 and 255: ubiquitous chaperone that promotes
Page 256 and 257: was thought that they are linked to
Page 258 and 259: pathologic induction of miR-28 in M
Page 260 and 261: STATs. Second, levels of HP1 alpha
Page 262 and 263: 72. Irandoust MI, Aarts LH, Roovers
Page 264 and 265: A.M. Vannucchi Section of Hematolog
Page 266 and 267: 2,559 patients with a diagnosis of
Page 268 and 269: tant use of aspirin should be caref
Page 270 and 271: sions at this regard. Based on thes
Page 272 and 273: in bcr-abl-negative myeloproliferat
Page 274 and 275: Table 1. Prognostic scoring systems
Page 276 and 277: Figure 1. Current inhibitors of JAK
Page 278 and 279: Table 4. A risk-based approach to d
Page 280 and 281: the flexibility to be adjusted as t
Page 284 and 285: neovessel building together with MM
Page 286 and 287: Mevastatin, a specific inhibitor of
Page 288 and 289: egression of tumor vessels, and app
Page 290 and 291: diagnosis does not require genetic
Page 292 and 293: Genetics prognostic tools should be
Page 294 and 295: sone induction improves outcome of
Page 296 and 297: Table 1. Conventional chemotherapy
Page 298 and 299: Novel agents given as consolidation
Page 300 and 301: dence of peripheral neuropathy, gas
Page 302 and 303: 31. Barlogie B, Tricot G, Anaissie
Page 304 and 305: Table 1. Major differences between
Page 306 and 307: first line therapy have shown survi
Page 308 and 309: transplantation, 7,91 and generally
Page 310 and 311: methylation characterizes juvenile
Page 312 and 313: Table 1. Clinical signs of possible
Page 314 and 315: Table 4. Distribution of CSF involv
Page 316 and 317: ently results in a less than 5% cum
Page 318 and 319: 90. German-Austrian-Swiss ALL-BFM S
Page 320 and 321: U. Nowak-Göttl 1 R. Junker 1 A. Kr
Page 322 and 323: Based on the data obtained from the
Page 324 and 325: 59. Male C, Chait P, Ginsberg JS, e
Page 326 and 327: Table 1. Characteristic features of
Page 328 and 329: Table 2. Mutational spectrum of CDA
Page 330 and 331: megarakaryoblastic leukemia (AMKL)
Page 332 and 333:
R.E. Ware Professor and Vice-Chairm
Page 334 and 335:
protein, cytokines, and soluble adh
Page 336 and 337:
example, improving blood viscosity
Page 338 and 339:
92(9):1266-7. 36. Bensinger TA, Gil
Page 340 and 341:
London, United Kingdom, June 9-12,
Page 342 and 343:
port have also been used. 5 Combina
Page 344 and 345:
Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347:
K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349:
include the childhood infectious il
Page 350 and 351:
Summary Patients undergoing hematop
Page 352 and 353:
Table 1. Key issues. In a retrospec
Page 354 and 355:
invasive method to assess iron over
Page 356 and 357:
stitution but even with optimal sub
Page 358 and 359:
T.M. Hackeng Department of Biochemi
Page 360 and 361:
and inhibits FVIIa, and that the se
Page 362 and 363:
Figure 4. Regulation of coagulation
Page 364 and 365:
T. Baglin Department of Haematology
Page 366 and 367:
Figure 1. Illustration of alternati
Page 368 and 369:
compared with 3.5% in patients with
Page 370 and 371:
49. Hron G, Kollars M, Binder BR, E
Page 372 and 373:
Women receiving vitamin K antagonis
Page 374 and 375:
molecular weight heparin as prophyl
Page 376 and 377:
eral morbidity and mortality. 17-21
Page 378 and 379:
the HOD construct. Furthermore, the
Page 380 and 381:
Goals of future murine studies incl
Page 382 and 383:
F. Noizat-Pirenne C. Tournamille Et
Page 384 and 385:
phenotype. 26 In 2010, we investiga
Page 386 and 387:
ody has been involved in DHTR. 37 T
Page 388 and 389:
antigen. Cases can be encountered d
Page 390 and 391:
S.R. Sloan Harvard Medical School &
Page 392 and 393:
We also analyzed patient databases
Page 394 and 395:
Index of authors Altman J. 27 Bacig
Page 396 and 397:
Cornelissen J. Affiliations to disc
Page 398 and 399:
GlaxoSmithKline (Research Support;
show all

H e m a t o lo g y E d u c a t io n - European Hematology Association

Create successful ePaper yourself

Delete template?

Save as template?