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

More documents

Recommendations

Info

ern era of BCR-ABL1 tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood. 2008; 11:1774-80. 20. Quintas-Cardama A, Cortes J, O’Brien S, et al. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer. 2009;115:2912-21. 21. Kantarjian H, Giles F, Bhalia K et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2010 November 22. [Epub ahead of print as doi: 10.1182/blood-2010-03-277152] 22. Hochhaus A, Kantarjian H, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303-9. 23. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL1 with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95:232-40. 24. Cortes J, Kantarjian H, Brummendort TH, et al. Safety and efficacy of bosutinib (SKI-606) in patients with chronic phase chronic myeloid leukemia following resistance or intolerance to imatinib. J Clin Oncol 2010;28:Abstract 6502. 25. Kantarjian H, O’Brien S, Talpaz M, et al. Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer. 2007;109: 1556-60. 26. Verma D, Kantarjian H, Jones D, Luthra R, Borthakur G, Verstovsek S, et al. Chronic myeloid leukemia (CML) with P190BCR-ABL1: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009;114:2232-5. 27. Verma D, Kantarjian H, Shan J, O’Brien S, Estrov Z, Garcia- Manero G, et al. Survival outcomes for clonal evolution in London, United Kingdom, June 9-12, 2011 chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. Cancer. 2010;116:2673-81. 28. Jabbour E, Jones D, Kantarjian H, O’Brien S, Tam C, Koller C, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL1 kinase domain mutations. Blood. 2009;114:2037-43. 29. Hochhaus A, Muller MC, Cortes JE, Kim DW, Matloub Y, Ploughman L et al. Dasatinib efficacy after imatinib failure by dosing schedule and baseline BCR-ABL1 mutation status in patients with chronic myeloid leukemia in chronic phase (CML-CP). Haematologica. 2008;93: 371-2. 30. Tam C, Kantarjian H, Garcia-Manero G, Borthakur G, O’Brien S, Ravandi F, et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood. 2008;112: 516-8. 31. Cortes J, Talpza M, Bixby D, Deininger M, et al. A phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: emerging safety and clinical response findings. Blood. 2010;115:Abstract 210. 32. Van Etten RA, Chan WW, Zaleskas VM, et al. DCC-2036: A novel switch pocket inhibitor of ABL tyrosine kinase with therapeutic efficacy against BCR-ABL1 T315I in vitro and in a CML mouse model. Blood. 2007;110:Abstract 463. 33. Cortes J, Wetzler M, Lipton J, et al. Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure. Blood. 2010;116:Abstract 2290. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 131 |
E.V. Verovskaya 1,2 G. de Haan 1,2 1 Department of Cell Biology, section Stem Cell Biology; 2 European Research Institute on the Biology of Aging, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Acknowledgements: The authors would like to thank Leonid V. Bystrykh, Brad J. Dykstra, Ronald van Os and Hein Schepers, Department of Cell Biology, Section Stem Cell Biology, University Medical Centre Groningen for critical reading of the manuscript and valuable comments. Funding: This work was supported by a grant of the Netherlands Organization for Scientific Research (TopTalent, 021-002-084 (E.V.), and VICI, 918-76-601 (G.d.H.)), and by the European Community (EuroSystem, 200720). Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:132-139 Hematopoietic stem cells The power of diversity: hematopoietic stem cell heterogeneity and its clinical relevance Introduction More than 10 11 blood cells are produced daily in the process of hematopoiesis. 1 The turnover of these cells is assured by the enormous proliferative capacity of hematopoietic stem cells (HSCs) residing in the bone marrow. HSCs are capable of generating and regenerating at least nine distinct types of mature blood cells in the complex process of differentiation (Figure 1). The current prevailing view implies that during hematopoiesis, HSCs undergo several unidirectional division steps in which they generate distinct intermediate cell populations 2 and gradually lose their ability to self-renew. The ability for self-renewal and multilineage differentiation is the unique feature of HSCs. Traditionally, it has been assumed that all stem cells possess similar developmental potential and are equally capable of producing cells of all lineages (Figure 1). Multiple strategies were developed that were aimed to purify a homogeneous stem cell population, where each and every single stem cell possessed equal potential. However, the notion of stem cell homogeneity was challenged by data indicating a high level of heterogeneity of murine HSCs in terms of differentiation program, 3,4 repopulating capacity, 5,6 and turnover rate. 7,8 Although much effort is put in uncovering improved ways to characterize and (prospectively) isolate the putative hematopoietic stem cell, a growing body of data points out that THE hematopoietic stem cell does not exist. In contrast, intrinsic heterogeneity may be a key characteristic of HSCs. Existence of stem cells with different behavior provides a new perspective on cur- A B S T R A C T Multiple subsets of functionally distinct hematopoietic stem cells (HSCs) have recently been identified in murine studies. Individual HSCs can differ in their potential to generate certain mature blood cell lineages, repopulating capacity, and turnover rate. Changes in the clonal representation of distinct HSC subsets in the bone marrow are associated with aging and certain types of hematopoietic disorders. Therefore, understanding and addressing HSC heterogeneity is of major clinical importance and may lead to the development of superior treatment protocols. For instance, HSC transplantations should ensure re-establishment of a heterogeneous HSC pool in recipient patients. Although heterogeneity in the stem cell pool has been studied less extensively in humans than in mice, clonal tracking in recent gene therapy trials serves as an important source of information on stem cell behavior. Development of novel barcoding and deep sequencing technologies can provide more detailed and quantitative data on stem cell clonality. rent views of normal and pathological hematopoiesis. Recent data on HSC heterogeneity suggests that the equilibrium of different stem cell subsets can be crucial in maintaining blood homeostasis, while the clonal disbalance of HSC underlies abated hematopoietic function in aging and disease. Although evidence for intrinsic heterogeneity of the HSC compartment originates from studies in mice, there is no reason to assume that a similar extent of heterogeneity is absent in human HSCs. Understanding the facets of HSC heterogeneity in humans is important to ensure both the current and future success of stem cell therapies and for the apprehension of blood disorders, such as various types of leukemias and other proliferative and dysplastic bone marrow diseases. The unique opportunity to track individually marked human HSCs provided by gene therapy trials, combined with rapid development of high-throughput sequencing analysis, holds great promise to obtain insight in such cellular heterogeneity. In the current review, we will address recent advances in our understanding of HSC heterogeneity and will highlight putative clinical consequences. HSC heterogeneity Stem cells comprise less than 0.01% of all bone marrow cells and are morphologically very difficult to distinguish from progenitor cells. HSCs can be partly characterized by immunophenotype, but unlike, for instance, the situation in the intestine, where Lgr5 can be used as a single stem cell marker, 9 such mono-markers have neither been found in | 132 | 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 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 282 and 283:
A. Vacca 1 D. Ribatti 2 1 Departmen
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?