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Chronic Myeloproliferative Disorders—Introduction
Volume 42, Number 4
October 2005
Chronic Myeloproliferative Disorders—Introduction
S
ince 1951, when the concept of myeloproliferative disorders (MPD) was first proposed by Dameshek,1 the diagnostic criteria for MPD have been constantly refined and modified.2– 4 The discovery of the Philadelphia chromosome and the BCR/ABL fusion gene in chronic myeloid leukemia (CML) led to the development of reliable molecular diagnostic tools and a specific inhibitor that targets the activated ABL kinase activity and is widely used in clinical practice today. CML is now considered a separate entity and will not be covered in this issue. The elucidation of the molecular basis of disease-causing mutations in the three remaining MPD entities, polycythemia vera (PV), essential thrombocytosis (ET), and idiopathic myelofibrosis (IMF), is a holy grail to which researchers aspire. As shown in this issue of Seminars in Hematology, our understanding of the pathophysiology of PV, IMF, and ET has progressed and large controlled clinical studies have recently addressed some of the longstanding therapeutic controversies. However, despite the advances, many questions remain unresolved. The most recent revision of the diagnostic criteria for MPD, published as the “World Health Organization (WHO) classification,” underscored the importance of histopathology and also included endogenous erythroid colonies (EECs) as criteria in assigning patients to the three main categories of MPD (PV, ET, and IMF).4 However, the interpretation and application of these criteria still causes considerable controversy among experts in the field, as witnessed by several articles in this issue of Seminars. One approach (see chapter by Thiele, Kvasnicka, and Orazi) assumes that a considerable proportion of ET patients are “misdiagnosed cases of prefibrotic IMF” and also proposes that most cases of PV and ET in patients who later develop secondary myelofibrosis should be regarded as IMF. These diagnostic decisions are important, since IMF often has a poor prognosis that justifies treatment by allogeneic (nonmyeloablative) stem cell transplantation (see chapter by Barosi and Hoffman). Contrary to this “IMF-centric view,” other investigators believe that secondary myelofibrosis is part of the natural history of PV and that many patients who first present in the “spent phase” of PV are currently being wrongly classified as having IMF (see chap0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.08.004
ters by Tefferi and Spivak, as well as Bench and Pahl). This “PV-centric view” also suggests that patients with ET who display EECs are actually cases of PV that have not yet developed elevated red cell mass (see chapter by Bench and Pahl), or cases where the diagnosis of PV was missed because measurement of red cell mass was not performed (see chapter by Tefferi and Spivak). At present, ET does not have a strong partisan lobby, in part because ET remains a diagnosis of exclusion. These diagnostic uncertainties complicate the interpretation of clinical data concerning the prognosis and rate of complications in individual MPD entities. As long as the diagnostic algorithms are based in part on personal opinions and until controlled studies replace anectodal evidence, the discussions will continue to have, at times, a religious character. As demonstrated in the case of CML, these issues will most likely be resolved once we know more about the primary molecular alterations that define the pathogenesis of individual MPD entities. Although clonality of peripheral blood cells has long been recognized as a defining feature of MPD, there is a considerable controversy as to its significance in the genesis of MPD. Some of these conflicts stem from differences in weighting the methodologic limitations of the assays to measure Xchromosome inactivation and the epigenetic factors that can modify the read-out of these assays. DNA-based clonality assays examine the methylation status of various genes on the X chromosome, such as PGK, HPRT, m27, and the human androgen receptor gene (HUMARA), based on the premise that hypermethylation caused X-chromosome inactivation.5 However, this approach may be confounded by environmental effects on the DNA methylation status and in some instances the lack of correlation between methylation status and X-chromosome gene inactivation.6,7 An assay that truly discriminates alleles of genes located on the active X-chromosome (those being transcribed) from alleles located on the inactivated X-chromosome (those that were silenced) is based on direct measurement of their mRNA transcripts.8,9 Several genes on the X chromosome with frequent allelic variants (polymorphisms) have been identified that are transcribed and detectable in the corresponding mRNA; in their 181
R. Skoda and J.T. Prchal
182 aggregate, these markers are informative for clonality studies in greater than 95% of females.10 Using these expressionbased clonality assays, all informative females we studied with PV had clonal reticulocytes, granulocytes, platelets, and at times B lymphocytes. However, T and natural killer cells were always polyclonal,11 albeit a small proportion of T lymphocytes appear to be part of the polycythemia vera clone.12 In addition to polyclonal hematopoiesis in secondary polycythemia, thrombocytosis, and secondary marrow fibrosis,13 polyclonal hematopoiesis in PV and IMF has also been reported.14 Whether these discrepancies are due to differences in the selection of patients or methodology remains to be resolved. The assessment of clonality in ET is less controversial. As described in the chapter on ET (Finazzi and Harrison), and in the chapter on “Chromosomal Abnormalities and Molecular Markers” (Bench and Pahl), a significant proportion of the females with typical ET phenotype have polyclonal hematopoiesis regardless of the methodology used.15 Importantly, it appears that the ET patients with polyclonal hematopoiesis have less morbidity than those with clonal hematopoiesis.16,17 Some suggest that only patients with clonal hematopoiesis should be considered “true ET” and they propose that patients with polyclonal hematopoiesis should be placed into a new diagnostic category. However, such a classification would require clonality assays that are gender-independent and informative for all patients. Despite the controversies that concern diagnostic criteria, major progress has been made through recent prospective randomized studies in ET that now provide a rational basis for important treatment decisions (see chapter by Finazzi and Harrison). The recent discovery of a mutation in the Janus kinase 2 (JAK2) gene that leads to the substitution of a valine to phenylalanine at position 617 of the JAK2 protein (JAK2-617F) has transformed the MPD field (see chapter by Zhao et al). This mutation is acquired in hematopoietic cells only and therefore represents a clonality marker that is independent of gender. The frequencies of the JAK2-V617F mutation de-
rived from 10 reports published to date are summarized in Table 1. The JAK2-V617F mutation is most common in PV, followed by IMF and is least frequent in ET. In some patients only a small percentage of peripheral blood cells appear to carry the mutation, as suggested by the higher frequency of JAK2-V617F found in PV and ET (but not IMF) by a more sensitive allele-specific polymerase chain reaction (PCR) (Table 1).19 Interestingly, the mutation was also present at low frequencies in patients with atypical MPD, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS),23,24,26 but was not found in patients with CML, secondary erythrocytosis, acute lymphocytic leukemia, chronic lymphocytic leukemia or healthy individuals.23,24,26,27 What makes the JAK2 mutation so special? For one, it is the first reported acquired somatic mutation in hematopoietic progenitor or stem cells in these disorders. In contrast, other purported specific abnormalities, including aberrant gene expression (PRV1, MPL, NF-E2, BCL-XL) or subcellular localization (PTP-MEG2), were not associated with mutations of these genes, which raises the reasonable suspicion that these alterations are secondary events. This conclusion is supported by a recent report, which showed that elevated expression of PRV-1, NF-E2 and other marker genes correlated with the presence of JAK2-V617F or exogenous JAK2 stimulation by cytokines.28 Other publications also open the possibility that EECs may be a direct consequence of the presence of JAK2-V617F,21,25 and similarly, the decrease in MPL protein on platelets might be linked to the JAK2 mutation (see chapter by Zhao et al). Second, the finding that mice transplanted with bone marrow retrovirally transduced with JAK2-V617F developed erythrocytosis is so far the strongest indication that the mutation can cause a MPD phenotype.18 Finally, the invariant nature of the JAK2-V617F mutation (no other mutations in JAK2 have been described to date) makes it attractive to search for inhibitors that are specific for the activated mutant JAK2. However, while the discovery of JAK2 mutation is of undeniable importance, some mysteries will have to be solved. Why is this mutation associated with the
Table 1 Frequencies of the JAK2-V617F Mutation in Patients With Myeloproliferative Disorders Authors Data obtained by sequencing James et al.18 Baxter et al.19 Levine et al.20 Kralovics et al.21 Zhao et al.22 Jones et al.23* Steensma et al.24 Goerttler et al.25 Jelinek et al.26† Levine et al.27 Total Data obtained by allele-specific PCR Baxter et al.19
PV
IMF
ET
40/45 (89%) 53/73 (73%) 121/164 (74%) 83/128 (65%) 20/24 (83%) 58/81 (81%) ND 22/22 (100%) 25/29 (86%) ND 422/557 (76%)
3/7 (43%) 7/16 (44%) 16/46 (35%) 13/23 (57%) ND 15/35 (43%) ND 8/14 (57%) 18/19 (95%) ND 80/160 (50%)
9/21 (43%) 6/51 (12%) 37/115 (32%) 21/93 (23%) ND 24/59 (41%) ND 14/42 (33%) 3/10 (30%) ND 114/391 (29%)
8/16 (50%)
29/51 (57%)
71/73 (97%)
*Data obtained by the “amplification refractory mutation system” (ARMS). †Data obtained by pyrosequencing.
Introduction
183
MPDs of diverse phenotype and why do not all patients with JAK2-V617F display erythrocytosis? The occurrence of JAK2-V617F in chronic neutrophilic leukemia, MDS, and AML eludes an obvious rationale. In keeping with the Knudson hypothesis, it is possible that other somatic or germ-line mutations may interact with JAK2-V617F to create the observed disease phenotypes (see model depicted on the cover). Studies of familial MPD may prove to be particularly helpful in clarifying these aspects (see chapter by Skoda and Prchal). Thrombosis continues to be the major cause of morbidity and mortality in both PV and ET. While the role of low-dose aspirin was recently proven in the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) multicenter prospective clinical trial, this study also established that platelet activation plays a relatively small role in the thrombotic complications of MPDs. The contributions of elevated hematocrit in PV, neutrophil number and activation, and possible involvement of endothelial cells will need to be better defined (see chapter by Falanga et al). Clinical trials will be essential to validate the results obtained in molecular and retrospective studies (see chapter by Marchioli et al). A close interaction between basic and clinical research will be required to resolve the remaining controversial issues in the MPDs. We hope you will find this issue of Seminars and our attempts to summarize the current state of MPD research of value. Radek Skoda Josef T. Prchal Guest Editors
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
References 1. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 6:372, 1951 2. Murphy S: Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol 36:9-13, 1999 3. Pearson TC: Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol 38:21-24, 2001 4. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:22922302, 2002 5. Vogelstein B, Fearon ER, Hamilton SR, Feinberg AP: Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 227:642-645, 1985 6. Abrahamson G, Fraser NJ, Boyd J, Craig I, Wainscoat JS: A highly informative X-chromosome probe, M27 beta, can be used for the determination of tumour clonality. Br J Haematol 74:371-372, 1990 7. Allen AJ, Gale RE, Harrison CN, Machin SJ, Linch DC: Lack of pathogenic mutations in the 5=-untranslated region of the thrombopoietin gene in patients with non-familial essential thrombocythaemia. Eur J Haematol 67:232-237, 2001 8. Curnutte JT, Hopkins PJ, Kuhl W, Beutler E: Studying X inactivation. Lancet 339:749, 1992 9. Prchal JT, Guan YL, Prchal JF, Barany F: Transcriptional analysis of the active X-chromosome in normal and clonal hematopoiesis. Blood 81: 269-271, 1993 (letter) 10. Liu E, Jelinek J, Pastore YD, Guan Y, Prchal JF, Prchal JT: Discrimination of polycythemias and thrombocytoses by novel, simple, accurate
22.
23.
24.
25.
26.
27.
28.
clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood 101:3294-3301, 2003 Prchal JT: Polycythemia vera and other primary polycythemias. Curr Opin Hematol 12:112-116, 2005 Kralovics R, Guan Y, Prchal JT: Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 30:229-236, 2002 Popat U, Frost A, Reddy V, Liu E, May R, Bag R, Prchal JT: Myelofibrosis: New onset in association with pulmonary arterial hypertension. Ann Intern Med 143:466-467, 2005 Mitterbauer G, Winkler K, Gisslinger H, Geissler K, Lechner K, Mannhalter C: Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara). Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis. Am J Clin Pathol 112:93100, 1999 El Kassar N, Hetet G, Briere J, Grandchamp B: Clonality analysis of hematopoiesis in essential thrombocythemia: Advantages of studying T lymphocytes and platelets. Blood 89:128-134, 1997 Harrison CN, Gale RE, Machin SJ, Linch DC: A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood 93:417-424, 1999 Shih LY, Lin TL, Lai CL, Dunn P, Wu JH, Wang PN, et al: Predictive values of X-chromosome inactivation patterns and clinicohematologic parameters for vascular complications in female patients with essential thrombocythemia. Blood 100:1596-1601, 2002 James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, et al: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144-1148, 2005 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 365:1054-1061, 2005 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 7:387-397, 2005 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 352:1779-1790, 2005 Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, et al: Identification of an acquired JAK2 mutation in Polycythemia vera. J Biol Chem 280:2278822792, 2005 Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005, May 26 [Epub ahead of print] Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome. Blood 106:1207-1209, 2005 Goerttler PS, Kreutz C, Donauer J, Faller D, Maiwald T, Marz E, et al: Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2. Br J Haematol 129:138-150, 2005 Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S, et al: JAK2 mutation 1849G¡T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood 2005, Jul 21 [Epub ahead of print] Levine RL, Loriaux M, Huntly BJP, Loh ML, Beran M, Stoffgren E, et al: The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood 2005, Aug 4 [Epub ahead of print] Kralovics R, Teo SS, Buser AS, Brutsche M, Tiedt R, Tichelli A, et al: Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 2005, Aug 4 [Epub ahead of print]
October 2005
Chronic Myeloproliferative Disorders—Introduction
S
ince 1951, when the concept of myeloproliferative disorders (MPD) was first proposed by Dameshek,1 the diagnostic criteria for MPD have been constantly refined and modified.2– 4 The discovery of the Philadelphia chromosome and the BCR/ABL fusion gene in chronic myeloid leukemia (CML) led to the development of reliable molecular diagnostic tools and a specific inhibitor that targets the activated ABL kinase activity and is widely used in clinical practice today. CML is now considered a separate entity and will not be covered in this issue. The elucidation of the molecular basis of disease-causing mutations in the three remaining MPD entities, polycythemia vera (PV), essential thrombocytosis (ET), and idiopathic myelofibrosis (IMF), is a holy grail to which researchers aspire. As shown in this issue of Seminars in Hematology, our understanding of the pathophysiology of PV, IMF, and ET has progressed and large controlled clinical studies have recently addressed some of the longstanding therapeutic controversies. However, despite the advances, many questions remain unresolved. The most recent revision of the diagnostic criteria for MPD, published as the “World Health Organization (WHO) classification,” underscored the importance of histopathology and also included endogenous erythroid colonies (EECs) as criteria in assigning patients to the three main categories of MPD (PV, ET, and IMF).4 However, the interpretation and application of these criteria still causes considerable controversy among experts in the field, as witnessed by several articles in this issue of Seminars. One approach (see chapter by Thiele, Kvasnicka, and Orazi) assumes that a considerable proportion of ET patients are “misdiagnosed cases of prefibrotic IMF” and also proposes that most cases of PV and ET in patients who later develop secondary myelofibrosis should be regarded as IMF. These diagnostic decisions are important, since IMF often has a poor prognosis that justifies treatment by allogeneic (nonmyeloablative) stem cell transplantation (see chapter by Barosi and Hoffman). Contrary to this “IMF-centric view,” other investigators believe that secondary myelofibrosis is part of the natural history of PV and that many patients who first present in the “spent phase” of PV are currently being wrongly classified as having IMF (see chap0037-1963/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2005.08.004
ters by Tefferi and Spivak, as well as Bench and Pahl). This “PV-centric view” also suggests that patients with ET who display EECs are actually cases of PV that have not yet developed elevated red cell mass (see chapter by Bench and Pahl), or cases where the diagnosis of PV was missed because measurement of red cell mass was not performed (see chapter by Tefferi and Spivak). At present, ET does not have a strong partisan lobby, in part because ET remains a diagnosis of exclusion. These diagnostic uncertainties complicate the interpretation of clinical data concerning the prognosis and rate of complications in individual MPD entities. As long as the diagnostic algorithms are based in part on personal opinions and until controlled studies replace anectodal evidence, the discussions will continue to have, at times, a religious character. As demonstrated in the case of CML, these issues will most likely be resolved once we know more about the primary molecular alterations that define the pathogenesis of individual MPD entities. Although clonality of peripheral blood cells has long been recognized as a defining feature of MPD, there is a considerable controversy as to its significance in the genesis of MPD. Some of these conflicts stem from differences in weighting the methodologic limitations of the assays to measure Xchromosome inactivation and the epigenetic factors that can modify the read-out of these assays. DNA-based clonality assays examine the methylation status of various genes on the X chromosome, such as PGK, HPRT, m27, and the human androgen receptor gene (HUMARA), based on the premise that hypermethylation caused X-chromosome inactivation.5 However, this approach may be confounded by environmental effects on the DNA methylation status and in some instances the lack of correlation between methylation status and X-chromosome gene inactivation.6,7 An assay that truly discriminates alleles of genes located on the active X-chromosome (those being transcribed) from alleles located on the inactivated X-chromosome (those that were silenced) is based on direct measurement of their mRNA transcripts.8,9 Several genes on the X chromosome with frequent allelic variants (polymorphisms) have been identified that are transcribed and detectable in the corresponding mRNA; in their 181
R. Skoda and J.T. Prchal
182 aggregate, these markers are informative for clonality studies in greater than 95% of females.10 Using these expressionbased clonality assays, all informative females we studied with PV had clonal reticulocytes, granulocytes, platelets, and at times B lymphocytes. However, T and natural killer cells were always polyclonal,11 albeit a small proportion of T lymphocytes appear to be part of the polycythemia vera clone.12 In addition to polyclonal hematopoiesis in secondary polycythemia, thrombocytosis, and secondary marrow fibrosis,13 polyclonal hematopoiesis in PV and IMF has also been reported.14 Whether these discrepancies are due to differences in the selection of patients or methodology remains to be resolved. The assessment of clonality in ET is less controversial. As described in the chapter on ET (Finazzi and Harrison), and in the chapter on “Chromosomal Abnormalities and Molecular Markers” (Bench and Pahl), a significant proportion of the females with typical ET phenotype have polyclonal hematopoiesis regardless of the methodology used.15 Importantly, it appears that the ET patients with polyclonal hematopoiesis have less morbidity than those with clonal hematopoiesis.16,17 Some suggest that only patients with clonal hematopoiesis should be considered “true ET” and they propose that patients with polyclonal hematopoiesis should be placed into a new diagnostic category. However, such a classification would require clonality assays that are gender-independent and informative for all patients. Despite the controversies that concern diagnostic criteria, major progress has been made through recent prospective randomized studies in ET that now provide a rational basis for important treatment decisions (see chapter by Finazzi and Harrison). The recent discovery of a mutation in the Janus kinase 2 (JAK2) gene that leads to the substitution of a valine to phenylalanine at position 617 of the JAK2 protein (JAK2-617F) has transformed the MPD field (see chapter by Zhao et al). This mutation is acquired in hematopoietic cells only and therefore represents a clonality marker that is independent of gender. The frequencies of the JAK2-V617F mutation de-
rived from 10 reports published to date are summarized in Table 1. The JAK2-V617F mutation is most common in PV, followed by IMF and is least frequent in ET. In some patients only a small percentage of peripheral blood cells appear to carry the mutation, as suggested by the higher frequency of JAK2-V617F found in PV and ET (but not IMF) by a more sensitive allele-specific polymerase chain reaction (PCR) (Table 1).19 Interestingly, the mutation was also present at low frequencies in patients with atypical MPD, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS),23,24,26 but was not found in patients with CML, secondary erythrocytosis, acute lymphocytic leukemia, chronic lymphocytic leukemia or healthy individuals.23,24,26,27 What makes the JAK2 mutation so special? For one, it is the first reported acquired somatic mutation in hematopoietic progenitor or stem cells in these disorders. In contrast, other purported specific abnormalities, including aberrant gene expression (PRV1, MPL, NF-E2, BCL-XL) or subcellular localization (PTP-MEG2), were not associated with mutations of these genes, which raises the reasonable suspicion that these alterations are secondary events. This conclusion is supported by a recent report, which showed that elevated expression of PRV-1, NF-E2 and other marker genes correlated with the presence of JAK2-V617F or exogenous JAK2 stimulation by cytokines.28 Other publications also open the possibility that EECs may be a direct consequence of the presence of JAK2-V617F,21,25 and similarly, the decrease in MPL protein on platelets might be linked to the JAK2 mutation (see chapter by Zhao et al). Second, the finding that mice transplanted with bone marrow retrovirally transduced with JAK2-V617F developed erythrocytosis is so far the strongest indication that the mutation can cause a MPD phenotype.18 Finally, the invariant nature of the JAK2-V617F mutation (no other mutations in JAK2 have been described to date) makes it attractive to search for inhibitors that are specific for the activated mutant JAK2. However, while the discovery of JAK2 mutation is of undeniable importance, some mysteries will have to be solved. Why is this mutation associated with the
Table 1 Frequencies of the JAK2-V617F Mutation in Patients With Myeloproliferative Disorders Authors Data obtained by sequencing James et al.18 Baxter et al.19 Levine et al.20 Kralovics et al.21 Zhao et al.22 Jones et al.23* Steensma et al.24 Goerttler et al.25 Jelinek et al.26† Levine et al.27 Total Data obtained by allele-specific PCR Baxter et al.19
PV
IMF
ET
40/45 (89%) 53/73 (73%) 121/164 (74%) 83/128 (65%) 20/24 (83%) 58/81 (81%) ND 22/22 (100%) 25/29 (86%) ND 422/557 (76%)
3/7 (43%) 7/16 (44%) 16/46 (35%) 13/23 (57%) ND 15/35 (43%) ND 8/14 (57%) 18/19 (95%) ND 80/160 (50%)
9/21 (43%) 6/51 (12%) 37/115 (32%) 21/93 (23%) ND 24/59 (41%) ND 14/42 (33%) 3/10 (30%) ND 114/391 (29%)
8/16 (50%)
29/51 (57%)
71/73 (97%)
*Data obtained by the “amplification refractory mutation system” (ARMS). †Data obtained by pyrosequencing.
Introduction
183
MPDs of diverse phenotype and why do not all patients with JAK2-V617F display erythrocytosis? The occurrence of JAK2-V617F in chronic neutrophilic leukemia, MDS, and AML eludes an obvious rationale. In keeping with the Knudson hypothesis, it is possible that other somatic or germ-line mutations may interact with JAK2-V617F to create the observed disease phenotypes (see model depicted on the cover). Studies of familial MPD may prove to be particularly helpful in clarifying these aspects (see chapter by Skoda and Prchal). Thrombosis continues to be the major cause of morbidity and mortality in both PV and ET. While the role of low-dose aspirin was recently proven in the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) multicenter prospective clinical trial, this study also established that platelet activation plays a relatively small role in the thrombotic complications of MPDs. The contributions of elevated hematocrit in PV, neutrophil number and activation, and possible involvement of endothelial cells will need to be better defined (see chapter by Falanga et al). Clinical trials will be essential to validate the results obtained in molecular and retrospective studies (see chapter by Marchioli et al). A close interaction between basic and clinical research will be required to resolve the remaining controversial issues in the MPDs. We hope you will find this issue of Seminars and our attempts to summarize the current state of MPD research of value. Radek Skoda Josef T. Prchal Guest Editors
11. 12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
References 1. Dameshek W: Some speculations on the myeloproliferative syndromes. Blood 6:372, 1951 2. Murphy S: Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia. Semin Hematol 36:9-13, 1999 3. Pearson TC: Evaluation of diagnostic criteria in polycythemia vera. Semin Hematol 38:21-24, 2001 4. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:22922302, 2002 5. Vogelstein B, Fearon ER, Hamilton SR, Feinberg AP: Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 227:642-645, 1985 6. Abrahamson G, Fraser NJ, Boyd J, Craig I, Wainscoat JS: A highly informative X-chromosome probe, M27 beta, can be used for the determination of tumour clonality. Br J Haematol 74:371-372, 1990 7. Allen AJ, Gale RE, Harrison CN, Machin SJ, Linch DC: Lack of pathogenic mutations in the 5=-untranslated region of the thrombopoietin gene in patients with non-familial essential thrombocythaemia. Eur J Haematol 67:232-237, 2001 8. Curnutte JT, Hopkins PJ, Kuhl W, Beutler E: Studying X inactivation. Lancet 339:749, 1992 9. Prchal JT, Guan YL, Prchal JF, Barany F: Transcriptional analysis of the active X-chromosome in normal and clonal hematopoiesis. Blood 81: 269-271, 1993 (letter) 10. Liu E, Jelinek J, Pastore YD, Guan Y, Prchal JF, Prchal JT: Discrimination of polycythemias and thrombocytoses by novel, simple, accurate
22.
23.
24.
25.
26.
27.
28.
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