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STATs. Second, levels of HP1 alpha bound to chromatin were found to be lower in embryonic stem (ES) cells engineered to express JAK2 V617F, and this effect was reversible upon addition of JAK2 inhibitors. Levels of phosphorylation of histone H3 tyrosine 41 were inversely correlated with HP1 alpha binding on chromatin. 120 Third, in mammalian hematopoietic cells, constitutive activation of STAT5, either by expression of JAK2 V617F, of TpoR W515 mutants, or of the active STAT5 1*6 mutant, 121 leads to induction of expression of the host gene for miR-28, Lipoma Preferred Partner (LPP), while acute STAT5 stimulation by cytokine did not. 45 This difference is due to the utilization of an alternative promoter containing a STAT5-binding site by the constitutively active STAT5 proteins. 45 Fourth, JAK2 V617F was shown to tyrosine phosphorylate and inhibit the catalytic activity of Protein Arginine Methyl Transferase 5 (PRMT5). 122 As a consequence, arginine methylation profiles of certain histones are altered in JAK2 V617F. A knock-down of PRMT5 leads in CD34-positive human cells to increased colony formation and erythroid differentiation, suggesting PRMT5 inactivation by JAK2 V617F might contribute to disease phenotype. It is, therefore, tempting to speculate that global chromatin changes are induced by constitutive JAK-STAT activation in MPNs and that these changes might play an important role in disease evolution. Conclusion The discovery of JAK2 V617F prompted attention towards the major feature of the majority of BCR-ABL negative MPNs, a constitutive active or aberrantly hyperactive JAK-STAT pathway. Since JAK2 is essential for formation of erythroid, megakaryocytic, and granulocytic myeloid cells, the trilineage expansion in these diseases could be well explained by the single JAK2 V617F event. More recently the picture became more complicated, with many other genetic events preceding or following the JAK2 V617F mutation, and with profound effects on chromatin that are only now beginning to be unraveled. While the understanding of the molecular bases of the phenotypes of diseases advanced rapidly, major unknowns remain with respect to signaling by JAK and receptor mutants in HSCs, epigenetic regulation induced by those mutants and mechanisms leading to leukemia transformation. Last but not least, reasons behind the acquisition of JAK2 V617F in HSCs remain completely unknown, as well as the molecular bases of MPN predisposition genes in families with MPNs. References 1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372-5. 2. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008 Jan;22(1):14-22. 3. Delhommeau F, Pisani DF, James C, Casadevall N, Constantinescu S, Vainchenker W. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006 Dec; 63(24):2939-53. 4. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med. 2006 Dec 7;355(23):2452-66. London, United Kingdom, June 9-12, 2011 5. Haeno H, Levine RL, Gilliland DG, Michor F. A progenitor cell origin of myeloid malignancies. Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16616-21. 6. Ugo V, Marzac C, Teyssandier I, Larbret F, Lecluse Y, Debili N, et al. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. Exp Hematol. 2004 Feb;32(2):179-87. 7. Kralovics R, Guan Y, Prchal JT. Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol. 2002 Mar;30(3):229-36. 8. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med. 1998 Feb 26;338(9):572-80. 9. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005 Apr 28;434(7037):1144-8. 10. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005 Mar 16;365(9464):1054-61. 11. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90. 12. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005 Apr;7(4):387-97. 13. Lu X, Huang LJ, Lodish HF. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F. J Biol Chem. 2008 Feb 29;283(9):5258-66. 14. Wernig G, Gonneville JR, Crowley BJ, Rodrigues MS, Reddy MM, Hudon HE, et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood. 2008 Apr 1;111(7):3751-9. 15. Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, et al. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest. 2010 Oct 1;120(10):3578-93. 16. Prodromou C, Pearl LH. Structure and functional relationships of Hsp90. Curr Cancer Drug Targets. 2003 Oct;3(5): 301-23. 17. Saharinen P, Silvennoinen O. The pseudokinase domain is required for suppression of basal activity of Jak2 and Jak3 tyrosine kinases and for cytokine-inducible activation of signal transduction. 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Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. Mol Cell. 2003;12(5):1239-50. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 251 |
16 th Congress of the European Hematology Association 28. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. Cytokine receptor signal transduction and the control of hematopoietic cell development. Ann Rev Cell Dev Biol. 1996;12:91-128. 29. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 1;356(5): 459-68. 30. Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011 Jan 11 [Epub ahead of print as doi:] 31. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006 Nov 15;108(10):3472-6. 32. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. 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Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007 Dec 13;1(6):685-97. 42. de Graaf CA, Kauppi M, Baldwin T, C DH, Metcalf D, Willson TA, et al. Regulation of hematopoietic stem cells by their mature progeny. Proc Natl Acad Sci U S A. 2010 Nov 29. [Epub ahead of print as doi:] 43. Moliterno AR, Spivak JL. Posttranslational processing of the thrombopoietin receptor is impaired in polycythemia vera. Blood. 1999 Oct 15;94(8):2555-61. 44. Moliterno AR, Williams DM, Rogers O, Spivak JL. Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression. Blood. 2006 Aug 15. 45. Girardot M, Pecquet C, Boukour S, Knoops L, Ferrant A, Vainchenker W, et al. miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets. Blood. 2010 Jul 22;116(3):437-45. 46. Besancenot R, Chaligne R, Tonetti C, Pasquier F, Marty C, Lecluse Y, et al. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 2010;8(9). 47. Dahlen DD, Broudy VC, Drachman JG. Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs. Blood. 2003 Jul 1;102(1):102-8. 48. Royer Y, Staerk J, Costuleanu M, Courtoy PJ, Constantinescu SN. Janus kinases affect thrombopoietin receptor cell surface localization and stability. J Biol Chem. 2005;280:27251-61. 49. Tiedt R, Coers J, Ziegler S, Wiestner A, Hao-Shen H, Bornmann C, et al. 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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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Page 212 and 213: Treatment strategies in germinal ce
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Page 220 and 221: Table 1. Diffuse Large B cell Lymph
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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
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Page 234 and 235: 38. Starczynowski DT, Morin R, McPh
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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
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Page 250 and 251: attainment of FDC post DLI. Interes
Page 252 and 253: myelodysplastic syndromes is associ
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Page 258 and 259: pathologic induction of miR-28 in M
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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
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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
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Page 296 and 297: Table 1. Conventional chemotherapy
Page 298 and 299: Novel agents given as consolidation
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Page 302 and 303: 31. Barlogie B, Tricot G, Anaissie
Page 304 and 305: Table 1. Major differences between
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
Page 344 and 345:
Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
Page 350 and 351:
Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
Page 356 and 357:
stitution but even with optimal sub
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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
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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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
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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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
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ody has been involved in DHTR. 37 T
Page 388 and 389:
antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
Page 392 and 393:
We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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