凋亡抑制蛋白Survivin在骨髓增殖性疾病中的表达及其意义
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摘要
第一部分Survivin在骨髓增殖性疾病中的表达及其意义
【目的】探讨Survivin在骨髓增殖性疾病的表达与临床相关性
【方法】采用western blot方法检测21例ET、12例PV、12例CML和5例正常对照骨髓单个核细胞Survivin的表达,采用K562细胞系作为阳性对照。以β-actin作为内参计算Survivin表达水平的相对值。应用线性回归分析Survivin表达与临床特征的相关性。
【结果】ET、PV和CML患者骨髓中分别有5例(23.8%)、8例(66.8%)和10例(83.3%)Survivin表达呈阳性,5例正常对照均为阴性。PV和CML组阳性率明显高于ET组(P=0.02和P=0.001)。各组总Survivin表达水平与外周血WBC、巨核细胞数呈显著正相关。分组分析显示,在CML中其水平与外周血WBC计数、外周血幼稚细胞比例均显著正相关,但ET、PV中无此相关性。PV组中Survivin表达与外周血Hb水平及PLT计数呈正相关,而CML中呈负相关。ET中Survivin表达与外周血WBC、Hb、PLT数、JAK2V617F以及骨髓幼稚细胞等均无显著相关性。
【结论】Survivin在CML和ET、PV中的不同表达反映了它在这些疾病中的不同作用。在CML中,Survivin的异常表达可能发生于原始阶段细胞并与外周血幼稚比例呈正相关,而PV和ET中在相对成熟阶段起作用。PV患者的高Hb的维持与Survivin的高表达有关,提示Survivin在红系过度和异常增生中起作用。
第二部分原发性血小板增多症的临床特点分析
为了解我国原发性血小板增多症(ET)患者临床特点及疾病自然过程,对本院1980年5月至2006年12月间诊治的ET患者进行回顾性分析。438例患者中,男201例,女237例,中位发病年龄48岁。有出血者101例(23.1%),有栓塞者86例(19.6%),同时有出血和血栓者13例(3.0%),脾大150例,肝大60例。无症状者149例(34%),在诊治其他疾病时发现者145例(33.1%)。初诊时中位血小板数为1000×109/L。255例做骨髓活检,以大而多分叶的成熟巨核细胞增生为主,其中51例局部伴有网状纤维增生。114例患者检出90例JAK2V617F突变阳性,阳性率78.9%。180例做染色体核型检查,6例(3.3%)染色体异常。261例随访＞12月,中位随访时间60月(12～300月)。17例(6.5%)进展为骨髓纤维化(MF)。1例转为真性红细胞增多症(PV)。1例6年后转为PV,20年后转为MF。转为急性单核细胞白血病(M5)、骨髓增生异常综合征(MDS)、多发性骨髓瘤(MM)各1例。ET是以血栓和出血为主要症状的慢性骨髓增殖性疾病,无症状者比例高,易漏诊误珍。主要进展为MF,大多预后较好。
第三部分180例原发性血小板增多症的细胞遗传学分析
【目的】总结我国原发性血小板增多症(ET)患者的细胞遗传学特点及其临床意义
【方法】对我院180例ET患者的细胞遗传学结果进行回顾性分析,并探讨特异性染色体畸变(Chromosomal Abnormalities,CA)的临床意义。
【结果】
1、细胞遗传学结果:应用常规染色体检查(Conventional Cytogenetics,CC)患者总体的克隆性CA检出率为3.3%;染色体数目畸变中最多见的是三体是6、11,其次为11、15、22;最多见的单体为21,其次为8、13、14、18、Y。染色体结构畸变中最常累及的长短臂是9q、11q、20q。常累及的断裂点是9q12-31、11q14、20q11～12、5q13-31。
2、相关的临床特点分析:核型正常组和核型异常组的临床特征未见显著性差异,治疗有效率前者高于后者。
【结论】
我国ET患者的CA发生率较西方国家稍低,以染色体数目和染色体片段的增减为主,很少发生易位改变。克隆性染色体异常多为单一克隆性异常或伴有其他亚克隆异常核型。CA可累及所有的染色体,我国ET患者中+8的发生率明显低于西方国家,而累及9和21号染色体的几率较高。
Objective To investigate the expression of Survivin and its clinical implication in CMPD.
Methods The expression of Survivin protein in bone marrow mononuclear cells was measured by western blot in 21 ET,12 PV and 12 chronic myelogenous leukemia(CML) patients as well as five healthy donors.K562 cells were tested as a positive control.β-actin was used as an internal control.The relative levels of Survivin expression in each sample were calculated by normalizing to the levels ofβ-actin.The correlation between Survivin expression levels and blood cell counts was determined by drawing the best-fit linear curve with Regression Analysis.
Results Survivin expression was observed in 23.3%(5 of 21) cases in ET, 66.8%(8 of 12) in PV and 83.3%(10 of 12) in CML,but undetected in the five healthy donors.The positive rate of Survivin expression in PV and CML was markedly higher than that in ET(P=0.02 and P=0.001) and healthy group. Survivin expression levels in all patients correlated with WBC count of peripheral blood and with megakaryocyte count of bone marrow.When analyzing 3 groups of CML,ET and PV separatively,we found that Survivin expression levels correlated with peripheral blood WBC count and with the percentage of peripheral blood blast cell in CML group,but not in ET and PV groups. However,Survivin expression levels in PV group was associated with the amount of Hb.In contrast,the levels of Survivinwere reverse to the amount of Hb in CML group.Moreover,the levels of Survivin in ET group has no significant relationship with WBC count,Hb,PLT count,JAK2V617F or the percentage of blast cell in bone marrow.
Conclusions The different profile of Survivin expression in CML,PV and ET might reflects its different roles in these diseases.In CML,the aberrant expression of Survivin might happen earlier in blast cell and correlated with the percentage of blast cells.The correlation of Survivin and Hb in PV suggests a role of Survivin in Excessive and abnormal erythropoiesis.
To summarize the clinical feature and natural course of essential thrombocy-themia (ET) in China,A retrospective analysis was conducted in ET patients treated in our hospital during May 1980 and December 2006.In this period,438 patients(201 males and 237 females with a median age 48 years) were diagnosed in our hospital, hemorrhage occurred in 101 cases(23.1%),thrombosis occurred in 86 cases(19.6%), and 13 cases(3.0%) had both hemorrhage and thrombosis.Splenomegaly occurred in 150 cases and hepatomegaly occurred in 60 cases.One hundred and forty-nine cases (34%) had no symptoms at diagnosis and 145 cases(33.1%) confirmed by routine blood tests due to other diseases.The median platelet count at diagnosis was 1,000×10~9 /L(533～3,740×10~9/L).Bone marrow biopsy was performed in 255 cases showing mainly increase of enlarged mature megakaryocytes with hyperlobulated nuclei and local proliferation of reticular fiber were revealed in 51 cases.JAK2V617F mutation was detected in 90(78.9%) of the 114 patients.Karyotype analysis was performed in 180 cases and 6 cases(3.3%) had clonal chromosomal aberrations.Two hundred and sixty-one patients were followed-up over 12 months with a median follow-up period of 60 months(range from 12 to 300 months).Seventeen cases(6.5%) evolved into marrow fibrosis(MF) and one case evolved into polycythemia vera(PV).One case evolved into PV after 6 years and MF after 20 years.Three cases developed acute monocyte leukemia(MS),myelodysplastic syndrome(MDS) and multiple myeloma (MM),respectively.ET is a chronic myeloproliferative disorder characterized predominately by thrombocytosis and hemorrhage.The percentage of asymptomatic cases is high.The main sequelae of ET is MF and most cases have good prognosis.
Objective To summarize the cytogenetic characteristics and their clinical significances of the patients with essential thrombocythemia(ET) in China.
Methods Cytogenetic findings of 180 patients with ET were retrospectively analysed and the clinical implications of specific chromosomal abnormalities(CA) were investigated.
Result
1.Cytogenetic findings:clonal CAs were detected in 6 of 180 patients(3.3%) by conventional cytogenetics(CC);In the numerical aberrations,the most common trisomies were 6,1 and the most common monosomies were 21,followed by 8, 13,14,18 and Y.In the structural aberrations,the most frequently involved arms were 9q,11q and 20q,and the most frequently involved breakpoints were 9q12～31,11q14,20q11～12 and 5q13～31.
2.Clinical implications:there was no significant difference between the clinical characteristics of chromosomal abnormalities group and normal control,however the latter have a higher efficiency in therapy.
Conclusions
The occurency of CA in patients with ET from China is mildly lower than those from western country.The chromosomes numerical aberrations and deletant or addend of chromosomes arms are main abnormal in CA,but translocation occur seldom.Clonal CAs often display single clonal CA or company with other subclonal CAs.All chromosomes can be involved in CAs.The occurancy of +8 in patients of ET from China is obviously lower than those from western country,but chromosome 9 and 21 can be involved more frequency.
【目的】探讨Survivin在骨髓增殖性疾病的表达与临床相关性
【方法】采用western blot方法检测21例ET、12例PV、12例CML和5例正常对照骨髓单个核细胞Survivin的表达,采用K562细胞系作为阳性对照。以β-actin作为内参计算Survivin表达水平的相对值。应用线性回归分析Survivin表达与临床特征的相关性。
【结果】ET、PV和CML患者骨髓中分别有5例(23.8%)、8例(66.8%)和10例(83.3%)Survivin表达呈阳性,5例正常对照均为阴性。PV和CML组阳性率明显高于ET组(P=0.02和P=0.001)。各组总Survivin表达水平与外周血WBC、巨核细胞数呈显著正相关。分组分析显示,在CML中其水平与外周血WBC计数、外周血幼稚细胞比例均显著正相关,但ET、PV中无此相关性。PV组中Survivin表达与外周血Hb水平及PLT计数呈正相关,而CML中呈负相关。ET中Survivin表达与外周血WBC、Hb、PLT数、JAK2V617F以及骨髓幼稚细胞等均无显著相关性。
【结论】Survivin在CML和ET、PV中的不同表达反映了它在这些疾病中的不同作用。在CML中,Survivin的异常表达可能发生于原始阶段细胞并与外周血幼稚比例呈正相关,而PV和ET中在相对成熟阶段起作用。PV患者的高Hb的维持与Survivin的高表达有关,提示Survivin在红系过度和异常增生中起作用。
第二部分原发性血小板增多症的临床特点分析
为了解我国原发性血小板增多症(ET)患者临床特点及疾病自然过程,对本院1980年5月至2006年12月间诊治的ET患者进行回顾性分析。438例患者中,男201例,女237例,中位发病年龄48岁。有出血者101例(23.1%),有栓塞者86例(19.6%),同时有出血和血栓者13例(3.0%),脾大150例,肝大60例。无症状者149例(34%),在诊治其他疾病时发现者145例(33.1%)。初诊时中位血小板数为1000×109/L。255例做骨髓活检,以大而多分叶的成熟巨核细胞增生为主,其中51例局部伴有网状纤维增生。114例患者检出90例JAK2V617F突变阳性,阳性率78.9%。180例做染色体核型检查,6例(3.3%)染色体异常。261例随访＞12月,中位随访时间60月(12～300月)。17例(6.5%)进展为骨髓纤维化(MF)。1例转为真性红细胞增多症(PV)。1例6年后转为PV,20年后转为MF。转为急性单核细胞白血病(M5)、骨髓增生异常综合征(MDS)、多发性骨髓瘤(MM)各1例。ET是以血栓和出血为主要症状的慢性骨髓增殖性疾病,无症状者比例高,易漏诊误珍。主要进展为MF,大多预后较好。
第三部分180例原发性血小板增多症的细胞遗传学分析
【目的】总结我国原发性血小板增多症(ET)患者的细胞遗传学特点及其临床意义
【方法】对我院180例ET患者的细胞遗传学结果进行回顾性分析,并探讨特异性染色体畸变(Chromosomal Abnormalities,CA)的临床意义。
【结果】
1、细胞遗传学结果:应用常规染色体检查(Conventional Cytogenetics,CC)患者总体的克隆性CA检出率为3.3%;染色体数目畸变中最多见的是三体是6、11,其次为11、15、22;最多见的单体为21,其次为8、13、14、18、Y。染色体结构畸变中最常累及的长短臂是9q、11q、20q。常累及的断裂点是9q12-31、11q14、20q11～12、5q13-31。
2、相关的临床特点分析:核型正常组和核型异常组的临床特征未见显著性差异,治疗有效率前者高于后者。
【结论】
我国ET患者的CA发生率较西方国家稍低,以染色体数目和染色体片段的增减为主,很少发生易位改变。克隆性染色体异常多为单一克隆性异常或伴有其他亚克隆异常核型。CA可累及所有的染色体,我国ET患者中+8的发生率明显低于西方国家,而累及9和21号染色体的几率较高。
Objective To investigate the expression of Survivin and its clinical implication in CMPD.
Methods The expression of Survivin protein in bone marrow mononuclear cells was measured by western blot in 21 ET,12 PV and 12 chronic myelogenous leukemia(CML) patients as well as five healthy donors.K562 cells were tested as a positive control.β-actin was used as an internal control.The relative levels of Survivin expression in each sample were calculated by normalizing to the levels ofβ-actin.The correlation between Survivin expression levels and blood cell counts was determined by drawing the best-fit linear curve with Regression Analysis.
Results Survivin expression was observed in 23.3%(5 of 21) cases in ET, 66.8%(8 of 12) in PV and 83.3%(10 of 12) in CML,but undetected in the five healthy donors.The positive rate of Survivin expression in PV and CML was markedly higher than that in ET(P=0.02 and P=0.001) and healthy group. Survivin expression levels in all patients correlated with WBC count of peripheral blood and with megakaryocyte count of bone marrow.When analyzing 3 groups of CML,ET and PV separatively,we found that Survivin expression levels correlated with peripheral blood WBC count and with the percentage of peripheral blood blast cell in CML group,but not in ET and PV groups. However,Survivin expression levels in PV group was associated with the amount of Hb.In contrast,the levels of Survivinwere reverse to the amount of Hb in CML group.Moreover,the levels of Survivin in ET group has no significant relationship with WBC count,Hb,PLT count,JAK2V617F or the percentage of blast cell in bone marrow.
Conclusions The different profile of Survivin expression in CML,PV and ET might reflects its different roles in these diseases.In CML,the aberrant expression of Survivin might happen earlier in blast cell and correlated with the percentage of blast cells.The correlation of Survivin and Hb in PV suggests a role of Survivin in Excessive and abnormal erythropoiesis.
To summarize the clinical feature and natural course of essential thrombocy-themia (ET) in China,A retrospective analysis was conducted in ET patients treated in our hospital during May 1980 and December 2006.In this period,438 patients(201 males and 237 females with a median age 48 years) were diagnosed in our hospital, hemorrhage occurred in 101 cases(23.1%),thrombosis occurred in 86 cases(19.6%), and 13 cases(3.0%) had both hemorrhage and thrombosis.Splenomegaly occurred in 150 cases and hepatomegaly occurred in 60 cases.One hundred and forty-nine cases (34%) had no symptoms at diagnosis and 145 cases(33.1%) confirmed by routine blood tests due to other diseases.The median platelet count at diagnosis was 1,000×10~9 /L(533～3,740×10~9/L).Bone marrow biopsy was performed in 255 cases showing mainly increase of enlarged mature megakaryocytes with hyperlobulated nuclei and local proliferation of reticular fiber were revealed in 51 cases.JAK2V617F mutation was detected in 90(78.9%) of the 114 patients.Karyotype analysis was performed in 180 cases and 6 cases(3.3%) had clonal chromosomal aberrations.Two hundred and sixty-one patients were followed-up over 12 months with a median follow-up period of 60 months(range from 12 to 300 months).Seventeen cases(6.5%) evolved into marrow fibrosis(MF) and one case evolved into polycythemia vera(PV).One case evolved into PV after 6 years and MF after 20 years.Three cases developed acute monocyte leukemia(MS),myelodysplastic syndrome(MDS) and multiple myeloma (MM),respectively.ET is a chronic myeloproliferative disorder characterized predominately by thrombocytosis and hemorrhage.The percentage of asymptomatic cases is high.The main sequelae of ET is MF and most cases have good prognosis.
Objective To summarize the cytogenetic characteristics and their clinical significances of the patients with essential thrombocythemia(ET) in China.
Methods Cytogenetic findings of 180 patients with ET were retrospectively analysed and the clinical implications of specific chromosomal abnormalities(CA) were investigated.
Result
1.Cytogenetic findings:clonal CAs were detected in 6 of 180 patients(3.3%) by conventional cytogenetics(CC);In the numerical aberrations,the most common trisomies were 6,1 and the most common monosomies were 21,followed by 8, 13,14,18 and Y.In the structural aberrations,the most frequently involved arms were 9q,11q and 20q,and the most frequently involved breakpoints were 9q12～31,11q14,20q11～12 and 5q13～31.
2.Clinical implications:there was no significant difference between the clinical characteristics of chromosomal abnormalities group and normal control,however the latter have a higher efficiency in therapy.
Conclusions
The occurency of CA in patients with ET from China is mildly lower than those from western country.The chromosomes numerical aberrations and deletant or addend of chromosomes arms are main abnormal in CA,but translocation occur seldom.Clonal CAs often display single clonal CA or company with other subclonal CAs.All chromosomes can be involved in CAs.The occurancy of +8 in patients of ET from China is obviously lower than those from western country,but chromosome 9 and 21 can be involved more frequency.
引文
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13朱霞.原发性血小板增多症8例临床分析.华夏医学,1999,12:55-56.
14文欣轩,王海云,王静,等.青年原发性血小板增多症误诊6例分析.中国误诊学杂志,2006,6:130-131.
15Landolfi R,Marchioli R,Kutti J,Gisslinger H,Tognoni G,Patrono C,Barbui T,European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators:Efficacy and safety of low-dose aspirin in polycythemia vera.N Engl J Med 2004,350:114-124.
16Low dose aspirin in polycythaemia vera:apilot study.Gruppo Italiano Studio Policitemia.Br J Haematol 1997,97:453-456.
17Randi ML,Rossi C,Fabris F,Menapace L,Girolami A:Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia.Clin Appl Thromb Hemost 1999,5:131-135.
18Van Genderen PJJ,Mulder PGH,Weleboer M,Van de Moesdijk D,Michiels JJ:Prevention and treatment of thrombotic complications in essential thrombocythaemia:efficacy and safety of aspirin.Br J Haematol 1997,97:179-84.
19Campbell PJ,Scott LM,Buck G,etal.Definition of subtypes ofessential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet, 2005, 366: 1945-1953.
20 Cervantes F, Alvarez-Larran A, Talarn C, et al. Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol, 2002, 118:786-790.
1. Murphy S, Peterson P, Hand H, Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol.1997;34(1):29-39
2. Mitelman F. An International System for Human Cytogenetic Nomenclature[M]. Basel: ISCN, 1995
3. U. Bacher, T. Haferlach, W. Kern, W. Hiddemann, S. Schnittger, C. Schoch, Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information, Ann. Hematol. 2005, (84) : 250-257.
4. El Kassar N, Hetet G, Briere J, Grandchamp B: Clonality analysis of haematopoiesis in essential thrombocythemia: advantages of studying T-lymphocytes and platelets. Blood 1997,89:128-134.
5. David P. Steensmaa,b Ayalew Tefferia. Cytogenetic and Molecular Genetic
6. Aspects of Essential Thrombocythemia. Acta Haematol 2002;108:55 - 65
7. Elis A, Amid A, Manor Y. et al. The deteetion of trisomies 8 an d 9 in patients with essential thrombocytosis by fluorescence in situ hybridization. Cancer Genet Cytogenet, 1996, 92(1): 14.
8. Uozumi K, Ohno N, Shimotakahara S, et al. Trisomy 8 in essential thrombocythemia in leukemic transformation. Cancer Genet Cytogenet.2000 Jan 1;116(1):84-6.
9. Munro LR, Stevenson DA, Culligan DJ. Translocation (X;5)(q13;q33) in essential thromcocythemia . Cancer Genet Cytogenet. 1999, 1;114:78-9
10. Bench AJ, Cross NCP, Huntly BJP, et al. Myeloproliferative disorders. Best Pract Res Clin Haematol 2001,14:531-551
11. Vassiliou GS, Campbell PJ, Li J. An acquired translocation in JAK2 Val617Phe-negative essential thrombocythemia associated with autosomal spread of X-inactivation. Haematologica, 2006, 91: 1 100—1 104
12. Reis MD, Sher GD, Lakhani A, et al. Deletionof the long arm of chromosome 5 in essential thrombocythemia.Cancer Genet Cytogenet,1992,61(1):93
13.宋君红,张苏江,李建勇.JAK2基因突变与慢性骨髓增殖性疾病[J].中华血液学杂志,2006.27(10):713.
14.Al-Assar O,Ul-Hassan A,Brown R,et al.Gains on 9p are common genomic aberrations in idiopathic myelofibrosis" a comparative genomic hybridization study.Br J Haematol.2005 Apr;129(1):66-71.
1 Baxter EJ, Scott LM, Campbell PJ, etal. Aquired mutation of thetyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 2005, 365: 1054-1061
2 Villeval JL, Jam es C, Pisan i DF, et al. New insights into the pathogenesis of JAK2 V617F positive myeloproliferative disorders and consequences for the management of patients. SemThromb Haemost, 2006, 32: 341—351.
3 Johansson P: Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. SeminThromb Hemost 2006, 32:171-173.
4 Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC: Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000, 65:132-139.
5 Teferi A. Recent progress in the pathogenesis and management of essential-ythemia. Leuk Res, 2001。 25: 369-377.
6 Chait Y, Condat B, Cazals-Hatem D, Rufat P, Atmani S, Chaoui D, Guilmin F,Kiladjian JJ, Plessier A, Denninger MH, Casadevall N, Valla D, Briere JB: Relevance of the criteria commonly used to diagnose myeloproliferative disorders in patients with splanchnic thrombosis. Br J Haematol 2005, 129:553-560
7 Michiels JJ, Berneman Z, Bockstaele DV, van der Planken M, De Raeve H,Schroyens W: Clinical and laboratory features, pathology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost 2006, 32:174-207.
8 Van Genderen PJJ, Budde U, Michiels JJ, van Strik R, van Vliet HHMD: The reduction of large von Willebrand factor multimeres in plama in essential thrombocythemia is related to the platelet count. Br J Haematol 1996, 93:362-965
9 Griesshammer M, Bangerter M, van Vliet HH, Michiels JJ: Aspirin in essential thrombocythemia: status quo and quo vadis. Semin Thromb Hemost 1997, 3:371-377.
10 Barbui T, Finazzi G, Dupuy E, Kiladjian JJ, Briere J: Treatment strategies in essential thrombocythemia. A critical appraisal of various experiences in different centers. Leuk Lymphoma 1996, 22(Suppl 1):149-160.
11 Griesshammer M, Heimpel H, Pearson T: Essential thrombocythemia and pregnancy.Leuk Lymphoma 1996, 22(Suppll):57-63.
12 Harrison C: Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br J Haematol 2005, 129:293-306.
13 Murphy S, Peterson P, Hand H, Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol.1997;34(1):29-39
14 Imbert M, Pierre R, Thiele J, Vardiman JW, Brunning RD, Flandrin G:Essential thrombocythaemia. In World Health Organization Classification of Tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues Edited by: Jaffe ES, Harris NL, Stein H, Vardiman JW.Lyon, IARC press; 2001:39-41.
15 Ayalew Tefferi, Juergen Thiele, Attilio Or.azi. Proposals and rationale for revision of theWorld Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primarymyelofibrosis:recommendations from an ad hoc international expert panel. BLOOD, 15 AUGUST 2007, 110: 4
16 Thiele J, Kvasnicka HM. A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders. Leuk Lymphoma.2006;47:381-396.
17 Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clin Proc. 2005;80:923-936.
18 Ruggeri M, Tosetto A, Frezzato M, Rodeghiero F. The rate of progression to polycythemia vera or 1096 TEFFERI et al BLOOD, 15 AUGUST 2007 _ VOLUME 110, NUMBER 4 essential thrombocythemia in patients with erythrocytosis or thrombocytosis. Ann Intern Med.2003;139:470-475.
19 Lengfelder E, Hochhaus A, Kronawitter U, et al. Should a platelet limit of 600 × 10(9)/1 be used as a diagnostic criterion in essential thrombocythaemia? An analysis of the natural course including early stages. Br J Haematol. 1998;100:15-23.
20 Sacchi S, Vinci G, Gugliotta L, et al. Diagnosis of essential thrombocythemia at platelet counts between 400 and 600x10(9)/L: Gruppo Italiano Malattie Mieloproliferative Croniche(GIMMC). Haematologica.2000;85:492-495.
21 Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc. 2005;80:947-958.
22 Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood.2005;106:2162-2168.
23 Thiele J, Kvasnicka HM. Clinicopathological criteria for differential diagnosis of thrombocythemias in various myeloproliferative disorders.Semin Thromb Hemost. 2006;32:219-230.
24 Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S,Beran M, Estey E, Kantarjian HM, Issa JP: JAK2 mutation 1849G >T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood 2005, 106:3370-3373.
25 Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, Sekeres MA,Maciejewski JP: Refractory anemia with ringed sideroblasts associted with marked thrombocytosis (RART), another myeloproliferative condition characterised by JAK2 V617F mutation. Blood 2006, 108:2173-2181
26 Campbell PJ, Green AR: Management of polycythemia vera and essential thrombocythemia. Hematology Am Soc Hematol Educ Program 2005:201-208.
27 Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M,Mazzucconi MG, Rodeghiero F, Tura S: Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004,89:215-232
28 Harrison C: Essential thrombocythaemia: challenges and evidence- based management. Br J Haematol 2005, 130:153-165.
29 Michiels JJ: Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia. Clin Appl Throm Hemost 1999, 5:247-251.
30 Elliott MA, Tefferi A: Thrombosis and haemorrhage in polycythemia vera and essential thrombocythaemia. Brh J Haematol 2005, 128:275-290.
31 Schwarz J, Pytlik R, Doubek M, Brychtova Y, Dulicek P, Campr V, Kren L,Penka M: Analysis of risk factors: the rationale of guidelines of the Czech Hematological Society for diagnosis and treatment of chronic myeloproliferative disorders with thrombocythemia. Sem Throm Hemost 2006,32:231-245.
32 Schafer AI: Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood 2006,107:4214-4222.
33 Landolfi R, Di Gennaro L, Novarese L, Patrono C: Aspirin for the control of platelet activation and prevention of thrombosis in essential thrombocythemia and polycythemia vera: current insights and rationale for futures studies. Semin Thromb Hemost 2006, 32:251-259.
34 Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C,Barbui T, European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004, 350:114-124.
35 Low dose aspirin in polycythaemia vera: a pilot study. Gruppo Italiano Studio Policitemia. Br J Haematol 1997,97:453-456.
36 Randi ML, Rossi C, Fabris F, Menapace L, Girolami A: Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia. Clin Appl Thromb Hemost 1999, 5:131-135.
37 Van Genderen PJJ, Mulder PGH, Weleboer M, Van de Moesdijk D, Michiels JJ: Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol 1997,97:179-84.
38 Ruggeri M, Castaman G, Rodeghiero F: Is Ticlopidine a safe alternative to management of myeloproliferative disorders. Haematologica 1993,78:18-21.
39 Cortclazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N EngI J Med 1995,332:1132-1136.
40 Harrison CN, Campbell PJ, Buck G, Wheat1ey K, East CL, Bareford, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR, United Kingdom Medical Research Council Primary Thrombocythemia 1 Study: Hydroxyurea compared to Anagrelide in High-risk essential thrombocythemia. N Engl J Med 2005, 353:33-45.
41 Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet, 2005, 366: 1945-1953.
42 Barosi G, Besses C, Birgegard G, et al. : A unified definition of clinical resistance/intolerance to Hydroxycarbamide in essential thrombocythemia:Results of a concensus process by an International Working Goup. Leukemia in press.
43 Fruchtman SM, Petitt RM, Gilbert HS, Fiddler G, Lyne A, Anagrelide Study Group: Anagrelide: analysis of long-term .efficacy, safety and eukemogenic potential in myeloproliferative disorders. Leuk Res 2005,29:481-491.
44 Samuelsson J, Hasselbalch H, Bruserud O, Temerinac S, Brandberg Y, Merup M, Linder O, Bjorkholm M, Pah1 HL, Birgegard G, Nordic Study Group for Myeloproliferative Disorders: A phase II trial of pegylated interferon alpha 2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life.Cancer 2006, 106:2397-2405.
45 Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrcli.de in high—risk essential thmmbOcvthemia. N Eng J Med, 2005,353:33-45.
46 Harrison C: Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br J Haematol 2005,129:293-306.
47 Martinelli P, Martinelli V, Agangi A, Maruotti GM, Paladini D, Ciancia R, Rotoli B: Interferon alfa treatment for pregnant women affected by essential thrombocythemia: case reports and a review. Am J Obstet Gynecol 2004, 191:2016-2020.
48 Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, Orlandi E, Arcaini L, Brusamolino E, Pascutto C, Cazzola M, Morra E,Lazzarino M: Life expectancy and prognostic factors for survival in polycythemia vera and essential thrombocythemia. Am J Med 2004,117:755-761.
49 Rozman C, Giralt M, Feliu E: Life expectancy of patients with chronic myeloproliferative disorders. Cancer 1991,67:2658-2663.
50 Cervantes F, Alvarez-Larran A, TalarnC, et al. Myelofibrosis withmyeloid metaplasia following essential thrombocythaemia: actuarial probability,presenting characteristics and evolution in a series of 195 patients. Br J Haematol, 2002, 118: 786-790.
2.Altieri DC,Marchislo PC,Marchisio C.Survivin apoptosis.,an interloper between cell death and cell proliferation in cancer.Lab Invest,1999,79(11)..1327-1333.
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14Altznauer F,Martinelli S,Yousefi S,Thurig C,Schmid I,Conway EM,Schoni MH,Vogt P,Mueller C,Fey MF,Zangemeister-Wittke U,Simon HU.Inflammation-associated cell cycle-independent block of apoptosis by Survivin in terminally differentiated neutrophils.J Exp Med 2004,199:1343-1354.
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1.Murphy S,Peterson P,IlandH,Experience of the PolycythemiaVeraStudy Group with essential thrombocythemia:a final report on diagnostic criteria,survival,and leukemic transition by treatment.SeminHematol.1997;34(1):29-39
2.杨仁池,华宝来,钱林生,等.原发性血小板增多症94例临床分析.临床血液学杂志,2000,13:8-10.
3.Ayalew Tefferi,Juergen Thiele,Attilio Orazi,et al.Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera,essential thrombocythemia,and primly myelofibrosis:recommendations from an ad hoc international expert panel.Blood,2007,110:1092-1097.
4.Teferi A.Recent progress in the pathogenesis and management of essential thrombocythemia.Leuk Res,2001,25::369-377.
5.ThieleJ,KvasnickaHM.Acritical reappraisal of the WHO classification of the chronic myeloproliferative disorders.Leuk Lymphoma.2006;47:381-396.
6.Tefferi A,Hanson CA,Inwards DJ.How to interpret and pursue an abnormal complete blood cell count in adults.Mayo Clin Proc.2005;80:923-936.
7.Ruggeri M,Tosetto A,Frezzato M,Rodeghiero F.The rate of progression to polycythemia vera or 1096 TEFFERI et al BLOOD,15 AUGUST 2007 _ VOLUME 110,NUMBER 4 essential thrombocythemia in patients with erythrocytosis or thrombocytosis.Ann Intern Med.2003;139:470-475.
8.Lengfelder E,Hochhaus A,Kronawitter U,et al.Should a platelet limit of 600 x 10(9)/1 be used as a diagnostic criterion in essential thrombocythaemia? An analysis of the natural course including early stages.Br J Haematol.1998;100:15-23.
9.Sacchi S,Vinci G,Gugliotta L,et al.Diagnosis of essential thrombocythemia at platelet counts between 400 and 600x10(9)/L:Gruppo Italiano Malattie Mieloproliferative Croniche(GIMMC).Haematologica.2000:85:492-495.
10Jaffe ES,Harris NL,Stein H,Vardiman JW,eds.Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues.Lyon,France:IARC Press;2001.World Health Organization Classification of Tumours:vol 3.
11Barbui T,Barosi G,Grossi A,et al.Practice guidelines for the therapy of essential thrombocythemia:a statement from the Italian Society of Hematology,the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica,2004,89:215-232.
12Chim CS,Kwong YL,Lie AK,et al.Long-term Outcome of 231 Patients With Essential Thrombocythemia Arch Intern Med,2005,165:2651-2658.
13朱霞.原发性血小板增多症8例临床分析.华夏医学,1999,12:55-56.
14文欣轩,王海云,王静,等.青年原发性血小板增多症误诊6例分析.中国误诊学杂志,2006,6:130-131.
15Landolfi R,Marchioli R,Kutti J,Gisslinger H,Tognoni G,Patrono C,Barbui T,European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators:Efficacy and safety of low-dose aspirin in polycythemia vera.N Engl J Med 2004,350:114-124.
16Low dose aspirin in polycythaemia vera:apilot study.Gruppo Italiano Studio Policitemia.Br J Haematol 1997,97:453-456.
17Randi ML,Rossi C,Fabris F,Menapace L,Girolami A:Aspirin seems as effective as myelosuppressive agents in the prevention of rethrombosis in essential thrombocythemia.Clin Appl Thromb Hemost 1999,5:131-135.
18Van Genderen PJJ,Mulder PGH,Weleboer M,Van de Moesdijk D,Michiels JJ:Prevention and treatment of thrombotic complications in essential thrombocythaemia:efficacy and safety of aspirin.Br J Haematol 1997,97:179-84.
19Campbell PJ,Scott LM,Buck G,etal.Definition of subtypes ofessential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet, 2005, 366: 1945-1953.
20 Cervantes F, Alvarez-Larran A, Talarn C, et al. Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol, 2002, 118:786-790.
1. Murphy S, Peterson P, Hand H, Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol.1997;34(1):29-39
2. Mitelman F. An International System for Human Cytogenetic Nomenclature[M]. Basel: ISCN, 1995
3. U. Bacher, T. Haferlach, W. Kern, W. Hiddemann, S. Schnittger, C. Schoch, Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information, Ann. Hematol. 2005, (84) : 250-257.
4. El Kassar N, Hetet G, Briere J, Grandchamp B: Clonality analysis of haematopoiesis in essential thrombocythemia: advantages of studying T-lymphocytes and platelets. Blood 1997,89:128-134.
5. David P. Steensmaa,b Ayalew Tefferia. Cytogenetic and Molecular Genetic
6. Aspects of Essential Thrombocythemia. Acta Haematol 2002;108:55 - 65
7. Elis A, Amid A, Manor Y. et al. The deteetion of trisomies 8 an d 9 in patients with essential thrombocytosis by fluorescence in situ hybridization. Cancer Genet Cytogenet, 1996, 92(1): 14.
8. Uozumi K, Ohno N, Shimotakahara S, et al. Trisomy 8 in essential thrombocythemia in leukemic transformation. Cancer Genet Cytogenet.2000 Jan 1;116(1):84-6.
9. Munro LR, Stevenson DA, Culligan DJ. Translocation (X;5)(q13;q33) in essential thromcocythemia . Cancer Genet Cytogenet. 1999, 1;114:78-9
10. Bench AJ, Cross NCP, Huntly BJP, et al. Myeloproliferative disorders. Best Pract Res Clin Haematol 2001,14:531-551
11. Vassiliou GS, Campbell PJ, Li J. An acquired translocation in JAK2 Val617Phe-negative essential thrombocythemia associated with autosomal spread of X-inactivation. Haematologica, 2006, 91: 1 100—1 104
12. Reis MD, Sher GD, Lakhani A, et al. Deletionof the long arm of chromosome 5 in essential thrombocythemia.Cancer Genet Cytogenet,1992,61(1):93
13.宋君红,张苏江,李建勇.JAK2基因突变与慢性骨髓增殖性疾病[J].中华血液学杂志,2006.27(10):713.
14.Al-Assar O,Ul-Hassan A,Brown R,et al.Gains on 9p are common genomic aberrations in idiopathic myelofibrosis" a comparative genomic hybridization study.Br J Haematol.2005 Apr;129(1):66-71.
1 Baxter EJ, Scott LM, Campbell PJ, etal. Aquired mutation of thetyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 2005, 365: 1054-1061
2 Villeval JL, Jam es C, Pisan i DF, et al. New insights into the pathogenesis of JAK2 V617F positive myeloproliferative disorders and consequences for the management of patients. SemThromb Haemost, 2006, 32: 341—351.
3 Johansson P: Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia. SeminThromb Hemost 2006, 32:171-173.
4 Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC: Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000, 65:132-139.
5 Teferi A. Recent progress in the pathogenesis and management of essential-ythemia. Leuk Res, 2001。 25: 369-377.
6 Chait Y, Condat B, Cazals-Hatem D, Rufat P, Atmani S, Chaoui D, Guilmin F,Kiladjian JJ, Plessier A, Denninger MH, Casadevall N, Valla D, Briere JB: Relevance of the criteria commonly used to diagnose myeloproliferative disorders in patients with splanchnic thrombosis. Br J Haematol 2005, 129:553-560
7 Michiels JJ, Berneman Z, Bockstaele DV, van der Planken M, De Raeve H,Schroyens W: Clinical and laboratory features, pathology of platelet-mediated thrombosis and bleeding complications and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost 2006, 32:174-207.
8 Van Genderen PJJ, Budde U, Michiels JJ, van Strik R, van Vliet HHMD: The reduction of large von Willebrand factor multimeres in plama in essential thrombocythemia is related to the platelet count. Br J Haematol 1996, 93:362-965
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