染色体分析在慢性骨髓增殖性疾病诊断及治疗中的应用
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摘要
目的：探讨染色体分析对慢性骨髓增殖性疾病(CMPD)分类、诊断及疗效判断的临床意义。
方法：收集CMPD患者骨髓细胞,采用24h常规培养法及R显带技术制备染色体标本,分析染色体核型改变,并对部分患者进行动态观察。
结果：①159例CMPD患者中染色体异常的检出率为69.18%,其中122例初诊为CML患者中,染色体异常的检出率为85.25%(104/122),37例初诊为其他类型的CMPD患者中,染色体异常的检出率为16.22%(6/37)。②CML慢性期与急变期和加速期患者出现额外染色体异常的比例分别为14.42%和61.11%,两者有显著性差异(X2=15.228,P<0.01)。③CML患者应用格列卫治疗与骨髓移植治疗后Ph染色体转阴率没有明显差异(X2=0.0178,P>0.05)。
结论：额外染色体异常的出现与CML病人的病程进展密切相关；染色体分析对CMPD的分型、诊断及疗效判断具有重要意义。
Objective:To investigate the clinical significance of chromosome analyzing in classification, diagnosis and efficacy to determine with the myeloproliferative disorders (CMPD).
Methods:Making a collection of bone marrow cells with CMPD were prepared by short-time culture, karyo-typing was performed by R-banding, dynamic detection of chromosomal changes were carried out in some patients in the course of progress.
Results:①The detection rate of chromosomal abnormality in 159 cases of CMPD patients was 69.18%, of which, in 122 cases of CML patients, was 85.25%(104/122), in 37 cases with newly diagnosed other types CMPD patients, the detection rate was 16.22% (6/37).②The rate of extra chromosome was found in 4.42% of patients in chronic phase (CP), and 61.11% in accelerated phase (AP) and blast crisis phase (BP), which had significant difference(X2=15.228, P<0.01).③Ph chromosome negative rate in CML patients with Gleevec therapy compared with bone marrow transplantation after treatment was not significantly different (X2=0.0178, P>0.05).
Conclusions:There is a close correlation between complex chromosome abnormalities and the progress of CML. Chromosome analysis plays an important role in the classification, diagnosis, and efficacy to determine of CMPD.
方法：收集CMPD患者骨髓细胞,采用24h常规培养法及R显带技术制备染色体标本,分析染色体核型改变,并对部分患者进行动态观察。
结果：①159例CMPD患者中染色体异常的检出率为69.18%,其中122例初诊为CML患者中,染色体异常的检出率为85.25%(104/122),37例初诊为其他类型的CMPD患者中,染色体异常的检出率为16.22%(6/37)。②CML慢性期与急变期和加速期患者出现额外染色体异常的比例分别为14.42%和61.11%,两者有显著性差异(X2=15.228,P<0.01)。③CML患者应用格列卫治疗与骨髓移植治疗后Ph染色体转阴率没有明显差异(X2=0.0178,P>0.05)。
结论：额外染色体异常的出现与CML病人的病程进展密切相关；染色体分析对CMPD的分型、诊断及疗效判断具有重要意义。
Objective:To investigate the clinical significance of chromosome analyzing in classification, diagnosis and efficacy to determine with the myeloproliferative disorders (CMPD).
Methods:Making a collection of bone marrow cells with CMPD were prepared by short-time culture, karyo-typing was performed by R-banding, dynamic detection of chromosomal changes were carried out in some patients in the course of progress.
Results:①The detection rate of chromosomal abnormality in 159 cases of CMPD patients was 69.18%, of which, in 122 cases of CML patients, was 85.25%(104/122), in 37 cases with newly diagnosed other types CMPD patients, the detection rate was 16.22% (6/37).②The rate of extra chromosome was found in 4.42% of patients in chronic phase (CP), and 61.11% in accelerated phase (AP) and blast crisis phase (BP), which had significant difference(X2=15.228, P<0.01).③Ph chromosome negative rate in CML patients with Gleevec therapy compared with bone marrow transplantation after treatment was not significantly different (X2=0.0178, P>0.05).
Conclusions:There is a close correlation between complex chromosome abnormalities and the progress of CML. Chromosome analysis plays an important role in the classification, diagnosis, and efficacy to determine of CMPD.
引文
1. Dameshek W. Some speculations on the myeloproliferative syn dromes. Blood,1951,6:372
2.周小鸽陈辉树主译.世界卫生组织肿瘤分类及诊断标准系列——造血与淋巴组织肿瘤病理学和遗传学[M].北京：人民卫生出版社,2001.35-38
3. Swerdlow SH, Campo E, Harris NL, et al. World Health Or ganization classification of tumours of the haematopoietic and lymphoid tissues. Lyon:Interational Agency for Research on Cancer, 2008,31-64
4.张之南,沈悌.血液病诊断及疗效标准[M].第3版.北京：科学出版社,2007：134-138.10
5. ISCN(1995).An international system for human cytogenetic normenclature, Mitelman Fed; Basel: Kanger,1995
6.周晓彬,纪新强,徐莉.医用统计学软件PPMS1.5的特点及其在医学科学研究中的应用[J].齐鲁医学杂志,2009,24(1)：92
7.谢新,过宇,薛永权.600例慢性粒细胞白血病的细胞遗传学分析.中华医学遗传学杂志,1998,15：85-88
8.姜道滋,陈志姝,楼基余等.1193例慢性粒细胞白血病细胞及分子遗传学分析.中华血液学杂志,2007,28(1)：1-5
9. HEIM S, BILLSTROM R,KRISTOFFERSSON U, et al. Variant Ph translation in chronic myeloid leukemia. Cancer Genet Cytogenent,1985,18:215-227
10. Francois Girodon, Gilles Bonicelli, Celine Schaeffer, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria:a population-based study. Haematologica,2009,94(6):865-869
11.杨颉,吴春梅,管洪在,赵洪国等.慢性粒细胞白血病染色体核型分析及其临床意义.青岛大学医学院学报,2009,45(1)：52-53,56
12. DRUKER BJ, TALPAZ M, RESTA DJ, et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia[J]. N Engl J Med,2001,344(14):1031.
13.金正明,吴德沛,孙爱宁.伊马替尼治疗Ph阳性慢性髓细胞白血病急变期及急性淋巴细胞白血病39例[J].实用临床医药杂志,2005,9(8)：53-54,56
14. Al-HUA WANG, YAN-YAN WANG, YU YAO, et al. Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006. Journal of Experimental & Clinical Cancer Research, 2010,29:20
15.李萍,管洪在,杨颉,王术国,吴春梅.格列卫对慢性粒细胞白血病病人Ph染色体和bcr/abll融合 基因表达影响[J].齐鲁医学杂志,2009,24(4)：289-291
16. Sophy Laibe, ZoulikaTadrist, Christine Arnoulet. A myeloproliferative disorder may hide another one. Leukemia Research,33 (2009):1133-1136
17.谢惠芳,徐如祥,魏继鹏JAK2/STAT3信号转导通路在缺血性脑损伤中作用机制的研究[J].《中风与神经疾病杂志》,2008,25(2)：135-138
18. James C, Ugo V, Couedic JP, et al. A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera. Nature,2005,434:1144-1148
19.潘湘涛,吴锦昌.JAK2基因突变与骨髓增殖性疾病[J].中国医学文摘·内科学.2006,27(4)：305-308
20. Windy BFMelanie J.McConnell RT. The Transcriptional Profile of PV Displays Limited Similarity to EPO Stimulated Progenitor Cells:Evidence That JAK2 V617F Confers a Novel Program to Malignant Hematopoietic Stem Cells [C].Blood (ASH Annual Meeting Abstracts),2005,106-120
1.薛永权.白血病细胞遗传学及图谱[M].天津科学技术出版社,2003：3,11
2. Tjio JH, Levan A. The chromosome number of man. Hereditas,1956,42:1-6
3. Ford CE, Jacobas P, Lajtha LG. Human somatic chromosomes. Nature,1958,181:1565-1568
4.薛志科,薛永权,棒宝爵.骨髓直接法、短期培养法和同步法在白血病染色体分析中的比较.中华医学遗传学杂志,1993,10(2)：102-103
5.柴局,刘淑英,张文广.荧光原位杂交技术在染色体上应用的研究进展.畜牧与饲料科学,200829(1)
6. Dameshek W. Some speculations on the myeloproliferative syn dromes. Blood,1951,6:372
7.周小鸽陈辉树主译.世界卫生组织肿瘤分类及诊断标准系列——造血与淋巴组织肿瘤病理学和遗传学[M].北京：人民卫生出版社,2001：35-38
8. Swerdlow SH, Campo E, Harris NL, et al. World Health Or ganization classification of tumours of the haematopoietic and lymphoid tissues. Lyon:Interational Agency for Research on Cancer,2008, 31-64
9.于亚平.骨髓增生肿瘤WH02008修订分类及临床诊断方法[J].现代肿瘤医学2009,17(4)：743-747
10. Nowell PC, Hungerford DA. A minute chromosome number of man. Hereditas,1956,42:1-6
11. Najfeld V, Montella L, Scalise A, etal. Exploring polycythaemia vera with fluorescence in situ hybridization:additional cryptic 9p is the most frequent abnormality detected[J]. Br J Haematol, 2002; 119(2):558-66
12. Lozyns'ka MP, Masliak ZV, Lukavets'kyi LM, etal. Prognostic significance of additional chromosomal abnormalities in Ph positive bone marrow cells in chronic myeloid leukemia[J]. Tsitol Genet,2005,39(1):26-33
13. Mesa R, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis(post-PV MF), post essential thrombocythemia myelofibrosis(post-ET MF), blast phase PMF(PMF-BP):Consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment(IWGMRT)[J]. Leukemia Res,2007,31(6):737-740
14. Reilly JT, Wilson G, Barnett D, Watmore A, Potter A. Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis. Br J Haematol,1994;88:575-81
15. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM,Jones N, Watmore A, Potter A. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis:a study of 106 cases. Br J Haematol,1997,98:96-102
16. Dingli D, Grand FH, Mahaffey V, et al. Der(6)t(1;6)(q21-23; p21.3):a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia[J]. Br J Haematol,2005,130(2):229-232
17.杨晓,王蔚,王艳.王春枝分子细胞生物技术诊断染色体病的研究进展.武警医学院学报,2008,17(12)：1137-1140
18. 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
19. Levine RL, Loriaux M, Huntly BJP, et al. Tth JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood,2005,106:3377-3379
20. Jelinek J, Oki Y, Gharibyan V, 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,2005,116:3370-3373
21. Goerttler PS, Steimle C, Marz E, et al. The Jak2V617F mutation, PRV-1 overexpression and EEC formation define a similar cohort of MPD patients. Blood,2005,106:2862-2864
22. Jones AV, Kreil S, zoi K, et al. Widespread occurrence of the JAK2V617F mutation in chronic myeloproliferative disorders. Blood,2005,106:2162-2168
23. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood,2005,106:1207-1209
24.潘湘涛,吴锦昌.JAK2基因突变与骨髓增殖性疾病[J].中国医学文摘·内科学.2006,27(4)：305-308
25. Windy BFMelanie J.McConnell RT. The Transcriptional Profile of PV Displays Limited Similarity to EPO Stimulated Progenitor Cells:Evidence That JAK2 V617F Confers a Novel Program to Malignant Hematopoietic Stem Cells [C].Blood (ASH Annual Meeting Abstracts)2005,106-120.
26. Withuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropo-itin receptor and is throsine phosphorylated and activated following stimulation with erythropoietin. Cell,1993, 74:227-236
27.夏珺,徐卫,张苏江等.特发性骨髓纤维化患者JAK2V617F和MPLW515L点突变及JAK2外显子12突变的研究.中华内科杂志,2009(2)：35-38
28. Lu X, Levine R, Tong W, et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc NAT1 Acad Sci U S A,2005,102(52):189
29. James C, Ugo V, Couedic JPL, et al. A unique clonal JAK2 mutation leading,to constitutive signaling causes polycythaemia vera. Nature,2005,434(7073):1144-1148
30. Garcon L, Rivat C, James C. et al. Constitutive activation of STATS and Bcl-xl overexpression can induce endogenous erthroid colony formation in human primary cells. Blood,2006,108(5): 1551-4
2.周小鸽陈辉树主译.世界卫生组织肿瘤分类及诊断标准系列——造血与淋巴组织肿瘤病理学和遗传学[M].北京：人民卫生出版社,2001.35-38
3. Swerdlow SH, Campo E, Harris NL, et al. World Health Or ganization classification of tumours of the haematopoietic and lymphoid tissues. Lyon:Interational Agency for Research on Cancer, 2008,31-64
4.张之南,沈悌.血液病诊断及疗效标准[M].第3版.北京：科学出版社,2007：134-138.10
5. ISCN(1995).An international system for human cytogenetic normenclature, Mitelman Fed; Basel: Kanger,1995
6.周晓彬,纪新强,徐莉.医用统计学软件PPMS1.5的特点及其在医学科学研究中的应用[J].齐鲁医学杂志,2009,24(1)：92
7.谢新,过宇,薛永权.600例慢性粒细胞白血病的细胞遗传学分析.中华医学遗传学杂志,1998,15：85-88
8.姜道滋,陈志姝,楼基余等.1193例慢性粒细胞白血病细胞及分子遗传学分析.中华血液学杂志,2007,28(1)：1-5
9. HEIM S, BILLSTROM R,KRISTOFFERSSON U, et al. Variant Ph translation in chronic myeloid leukemia. Cancer Genet Cytogenent,1985,18:215-227
10. Francois Girodon, Gilles Bonicelli, Celine Schaeffer, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria:a population-based study. Haematologica,2009,94(6):865-869
11.杨颉,吴春梅,管洪在,赵洪国等.慢性粒细胞白血病染色体核型分析及其临床意义.青岛大学医学院学报,2009,45(1)：52-53,56
12. DRUKER BJ, TALPAZ M, RESTA DJ, et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia[J]. N Engl J Med,2001,344(14):1031.
13.金正明,吴德沛,孙爱宁.伊马替尼治疗Ph阳性慢性髓细胞白血病急变期及急性淋巴细胞白血病39例[J].实用临床医药杂志,2005,9(8)：53-54,56
14. Al-HUA WANG, YAN-YAN WANG, YU YAO, et al. Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006. Journal of Experimental & Clinical Cancer Research, 2010,29:20
15.李萍,管洪在,杨颉,王术国,吴春梅.格列卫对慢性粒细胞白血病病人Ph染色体和bcr/abll融合 基因表达影响[J].齐鲁医学杂志,2009,24(4)：289-291
16. Sophy Laibe, ZoulikaTadrist, Christine Arnoulet. A myeloproliferative disorder may hide another one. Leukemia Research,33 (2009):1133-1136
17.谢惠芳,徐如祥,魏继鹏JAK2/STAT3信号转导通路在缺血性脑损伤中作用机制的研究[J].《中风与神经疾病杂志》,2008,25(2)：135-138
18. James C, Ugo V, Couedic JP, et al. A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera. Nature,2005,434:1144-1148
19.潘湘涛,吴锦昌.JAK2基因突变与骨髓增殖性疾病[J].中国医学文摘·内科学.2006,27(4)：305-308
20. Windy BFMelanie J.McConnell RT. The Transcriptional Profile of PV Displays Limited Similarity to EPO Stimulated Progenitor Cells:Evidence That JAK2 V617F Confers a Novel Program to Malignant Hematopoietic Stem Cells [C].Blood (ASH Annual Meeting Abstracts),2005,106-120
1.薛永权.白血病细胞遗传学及图谱[M].天津科学技术出版社,2003：3,11
2. Tjio JH, Levan A. The chromosome number of man. Hereditas,1956,42:1-6
3. Ford CE, Jacobas P, Lajtha LG. Human somatic chromosomes. Nature,1958,181:1565-1568
4.薛志科,薛永权,棒宝爵.骨髓直接法、短期培养法和同步法在白血病染色体分析中的比较.中华医学遗传学杂志,1993,10(2)：102-103
5.柴局,刘淑英,张文广.荧光原位杂交技术在染色体上应用的研究进展.畜牧与饲料科学,200829(1)
6. Dameshek W. Some speculations on the myeloproliferative syn dromes. Blood,1951,6:372
7.周小鸽陈辉树主译.世界卫生组织肿瘤分类及诊断标准系列——造血与淋巴组织肿瘤病理学和遗传学[M].北京：人民卫生出版社,2001：35-38
8. Swerdlow SH, Campo E, Harris NL, et al. World Health Or ganization classification of tumours of the haematopoietic and lymphoid tissues. Lyon:Interational Agency for Research on Cancer,2008, 31-64
9.于亚平.骨髓增生肿瘤WH02008修订分类及临床诊断方法[J].现代肿瘤医学2009,17(4)：743-747
10. Nowell PC, Hungerford DA. A minute chromosome number of man. Hereditas,1956,42:1-6
11. Najfeld V, Montella L, Scalise A, etal. Exploring polycythaemia vera with fluorescence in situ hybridization:additional cryptic 9p is the most frequent abnormality detected[J]. Br J Haematol, 2002; 119(2):558-66
12. Lozyns'ka MP, Masliak ZV, Lukavets'kyi LM, etal. Prognostic significance of additional chromosomal abnormalities in Ph positive bone marrow cells in chronic myeloid leukemia[J]. Tsitol Genet,2005,39(1):26-33
13. Mesa R, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis(post-PV MF), post essential thrombocythemia myelofibrosis(post-ET MF), blast phase PMF(PMF-BP):Consensus on terminology by the International Working Group for Myelofibrosis Research and Treatment(IWGMRT)[J]. Leukemia Res,2007,31(6):737-740
14. Reilly JT, Wilson G, Barnett D, Watmore A, Potter A. Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis. Br J Haematol,1994;88:575-81
15. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM,Jones N, Watmore A, Potter A. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis:a study of 106 cases. Br J Haematol,1997,98:96-102
16. Dingli D, Grand FH, Mahaffey V, et al. Der(6)t(1;6)(q21-23; p21.3):a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia[J]. Br J Haematol,2005,130(2):229-232
17.杨晓,王蔚,王艳.王春枝分子细胞生物技术诊断染色体病的研究进展.武警医学院学报,2008,17(12)：1137-1140
18. 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
19. Levine RL, Loriaux M, Huntly BJP, et al. Tth JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood,2005,106:3377-3379
20. Jelinek J, Oki Y, Gharibyan V, 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,2005,116:3370-3373
21. Goerttler PS, Steimle C, Marz E, et al. The Jak2V617F mutation, PRV-1 overexpression and EEC formation define a similar cohort of MPD patients. Blood,2005,106:2862-2864
22. Jones AV, Kreil S, zoi K, et al. Widespread occurrence of the JAK2V617F mutation in chronic myeloproliferative disorders. Blood,2005,106:2162-2168
23. Steensma DP, Dewald GW, Lasho TL, et al. The JAK2V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood,2005,106:1207-1209
24.潘湘涛,吴锦昌.JAK2基因突变与骨髓增殖性疾病[J].中国医学文摘·内科学.2006,27(4)：305-308
25. Windy BFMelanie J.McConnell RT. The Transcriptional Profile of PV Displays Limited Similarity to EPO Stimulated Progenitor Cells:Evidence That JAK2 V617F Confers a Novel Program to Malignant Hematopoietic Stem Cells [C].Blood (ASH Annual Meeting Abstracts)2005,106-120.
26. Withuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropo-itin receptor and is throsine phosphorylated and activated following stimulation with erythropoietin. Cell,1993, 74:227-236
27.夏珺,徐卫,张苏江等.特发性骨髓纤维化患者JAK2V617F和MPLW515L点突变及JAK2外显子12突变的研究.中华内科杂志,2009(2)：35-38
28. Lu X, Levine R, Tong W, et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc NAT1 Acad Sci U S A,2005,102(52):189
29. James C, Ugo V, Couedic JPL, et al. A unique clonal JAK2 mutation leading,to constitutive signaling causes polycythaemia vera. Nature,2005,434(7073):1144-1148
30. Garcon L, Rivat C, James C. et al. Constitutive activation of STATS and Bcl-xl overexpression can induce endogenous erthroid colony formation in human primary cells. Blood,2006,108(5): 1551-4