56例成人原发t（8；21）急性髓系白血病预后因素的分析
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摘要
急性髓系白血病(AML)是成人急性白血病中最常见的类型,t(8；21)急性髓性白血病(AML)占成人原发急性髓系白血病的6%,t(8；21)(q22；q22)是最常见的染色体易位方式之一。t(8；21)阳性的急性髓性白血病通常被认为是一类预后较好的白血病类型,但只有50-60%的患者可用目前方法治愈,还有一些病人,尽管予以化疗,病情仍迅速恶化。该病被认为具有异质性,因此,在诊断时对患者进行准确的临床预后分析评价,并实施个体化治疗方案,对提高患者的长期生存或治愈率具有重要意义。
影响t(8；21)急性髓系白血病患者预后的因素报道很多,然而大多数为就单一因素或其中几个因素的研究,本课题收集了56例成人原发性t(8；21)急性髓系白血病患者,从患者的临床特征、细胞遗传学、分子生物学和治疗等多方面综合研究,力求找出对此类患者的预后影响最大的因素,以期提高对患者的临床预后分析评价的准确性,并实施个体化治疗方案,提高患者的长期生存或治愈率。
首先用单因素分析的方法从患者的临床特征、细胞遗传学、分子生物学和治疗方面寻找对患者的总生存时间有影响的因素,发现初诊时外周血白细胞计数高、CD56高表达、基因突变(包括FLT3、KIT、TET2基因突变)及AE9a高表达量均是与患者生存期短有关的因素,而合并性染色体丢失者、CR1后使用大剂量阿糖胞苷巩固化疗者的生存时间相对较长。然后将上述六个因素共同做多因素cox回归模型分析,结果显示,对于患者生存时间影响具有统计学意义的独立因素为：是否存在KIT/TET2/FLT3基因突变和CR1后是否使用大剂量阿糖胞苷化疗。
分析对患者无病生存期影响因素的方法与上述类似,首先用单因素分析的方法从患者的临床特征、细胞遗传学、分子生物学和治疗方面找出对无病生存期有影响的因素,然后将上述因素纳入多因素cox回归模型分析,结果显示使用大剂量阿糖胞苷巩固治疗和初诊时白细胞计数则是影响患者无病生存期的独立因素。
本研究尽可能全面的分析了对成人原发性t(8；21)急性髓系白血病的预后(包括总生存时间和无病生存期)有影响的因素,并对各因素进行了多因素回归分析,结果发现是否存在KIT/TET2/FLT3基因突变和CR1后是否使用大剂量阿糖胞苷化疗是对于患者总生存时间影响具有统计学意义的独立因素,而使用大剂量阿糖胞苷巩固治疗和初诊时白细胞计数则是影响患者无病生存期的独立因素。
The balance translocation between chromosome eight and twenty-one [t(8;21) (q22;q22)] is one of the most common aberrant changes in patients with acute myeloid leukemia (AML). AML with t (8;21) composes 6% of adult de novo AML, and is be usually grouped as the favorable type. However, only 50-60% of t (8;21) AML patients could be cured. There might The heterogeneity of this kind of leukemia might be existed, and then it is important to discover its prognostic parameters and to adopt individualized therapy. There are many factors having been reported to be related with adult t (8;21) AML prognosis, but most of them were focused on one or a few of them. Fifty-six adult de novo AML patients with t(8;21) were enrolled in this study, and the information of their clinical features, cytogenetics, immunophenotype, gene mutations and treatment were collected. The outcomes of overall survival (OS) and disease-free survival(DFS) were analyzed with the above parameters.
Firstly, we analyzed the factors related to the OS of the patients by one variable analysis and found that high initial white blood cell counts on the diagnosis of the leukemia, gene mutations (including FLT3, KIT and TET2 gene mutation), CD56 strong expression and high AE9a expression were associated with shorter OS. On the other hand, complemented with loss of a sex chromosome and high dosage Ara-C (HD Ara-C) consolidation after complete remission might be related with longer OS. Then, we made multivariable cox regression analysis with these factors. The result showed that FLT3/KIT/TET2 gene mutations and HDAC were the most important independent factors for OS.
The same method was used to analyze the related factors for DFS. The possible determinants of DFS were firstly sorted out by one variable analysis, and then analyzed by using of multivariable cox regression analysis. The results were shown that HDAC and high white blood cell counts on the initail diagnosis of the disease were the most important independent factors for DFS.
Based on our research, we could conclude that FLT3/KIT/TET2 gene mutations and HD Ara-C chemotherapy were the most important independent factors for OS while HDAC and high white blood cell counts on the initial diagnosis of the disease were the most important independent factors for DFS.
影响t(8；21)急性髓系白血病患者预后的因素报道很多,然而大多数为就单一因素或其中几个因素的研究,本课题收集了56例成人原发性t(8；21)急性髓系白血病患者,从患者的临床特征、细胞遗传学、分子生物学和治疗等多方面综合研究,力求找出对此类患者的预后影响最大的因素,以期提高对患者的临床预后分析评价的准确性,并实施个体化治疗方案,提高患者的长期生存或治愈率。
首先用单因素分析的方法从患者的临床特征、细胞遗传学、分子生物学和治疗方面寻找对患者的总生存时间有影响的因素,发现初诊时外周血白细胞计数高、CD56高表达、基因突变(包括FLT3、KIT、TET2基因突变)及AE9a高表达量均是与患者生存期短有关的因素,而合并性染色体丢失者、CR1后使用大剂量阿糖胞苷巩固化疗者的生存时间相对较长。然后将上述六个因素共同做多因素cox回归模型分析,结果显示,对于患者生存时间影响具有统计学意义的独立因素为：是否存在KIT/TET2/FLT3基因突变和CR1后是否使用大剂量阿糖胞苷化疗。
分析对患者无病生存期影响因素的方法与上述类似,首先用单因素分析的方法从患者的临床特征、细胞遗传学、分子生物学和治疗方面找出对无病生存期有影响的因素,然后将上述因素纳入多因素cox回归模型分析,结果显示使用大剂量阿糖胞苷巩固治疗和初诊时白细胞计数则是影响患者无病生存期的独立因素。
本研究尽可能全面的分析了对成人原发性t(8；21)急性髓系白血病的预后(包括总生存时间和无病生存期)有影响的因素,并对各因素进行了多因素回归分析,结果发现是否存在KIT/TET2/FLT3基因突变和CR1后是否使用大剂量阿糖胞苷化疗是对于患者总生存时间影响具有统计学意义的独立因素,而使用大剂量阿糖胞苷巩固治疗和初诊时白细胞计数则是影响患者无病生存期的独立因素。
The balance translocation between chromosome eight and twenty-one [t(8;21) (q22;q22)] is one of the most common aberrant changes in patients with acute myeloid leukemia (AML). AML with t (8;21) composes 6% of adult de novo AML, and is be usually grouped as the favorable type. However, only 50-60% of t (8;21) AML patients could be cured. There might The heterogeneity of this kind of leukemia might be existed, and then it is important to discover its prognostic parameters and to adopt individualized therapy. There are many factors having been reported to be related with adult t (8;21) AML prognosis, but most of them were focused on one or a few of them. Fifty-six adult de novo AML patients with t(8;21) were enrolled in this study, and the information of their clinical features, cytogenetics, immunophenotype, gene mutations and treatment were collected. The outcomes of overall survival (OS) and disease-free survival(DFS) were analyzed with the above parameters.
Firstly, we analyzed the factors related to the OS of the patients by one variable analysis and found that high initial white blood cell counts on the diagnosis of the leukemia, gene mutations (including FLT3, KIT and TET2 gene mutation), CD56 strong expression and high AE9a expression were associated with shorter OS. On the other hand, complemented with loss of a sex chromosome and high dosage Ara-C (HD Ara-C) consolidation after complete remission might be related with longer OS. Then, we made multivariable cox regression analysis with these factors. The result showed that FLT3/KIT/TET2 gene mutations and HDAC were the most important independent factors for OS.
The same method was used to analyze the related factors for DFS. The possible determinants of DFS were firstly sorted out by one variable analysis, and then analyzed by using of multivariable cox regression analysis. The results were shown that HDAC and high white blood cell counts on the initail diagnosis of the disease were the most important independent factors for DFS.
Based on our research, we could conclude that FLT3/KIT/TET2 gene mutations and HD Ara-C chemotherapy were the most important independent factors for OS while HDAC and high white blood cell counts on the initial diagnosis of the disease were the most important independent factors for DFS.
引文
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29. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet.2009 Jul;41(7):838-42.
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1.方艳红, 刘红星,童春容.89例成人融合基因Aml1/Eto阳性急性髓系白血病长期生存分析.中国实验血液学杂志,2009：17(3)：750-755.
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4. Marcucci G, Mro'zek K, Ruppert AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16):a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23:5705-5717.
5. Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22):an additional deletion in 9q is an adverse prognostic factor. Leukemia.1996;10:1288-1295.
6. Haferlach T, Bennett JM, Loffler H, et al:Acute myeloid leukemia with translocation (8;21):Cytomorphology, dysplasia and prognostic factors in 41 cases. Leuk Lymphoma 23:227-234,1996.
7. Schlenk RF, Benner A, Krauter J, et al. Individual patient data2 based meta2analysis of patients aged 16 to 60 yearswith core binding factor acutemyeloid leukemia:a survey of the German AcuteMyeloid Leukemia Intergroup. J Clin Oncol,2004; 22:3741-3750.
1. Peterson LF, Boyapati A, Ahn EY, et al. Acute myeloid leukemia with the 8q22;21q22 translocation:secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110:799-805.This is a comprehensive review of secondary genetic alterations in CBF AML with t(8;21).
2. Mu" ller AMS, Duque J, Shizuru JA, Lu" bbert M. Complementing mutations in core binding factor leukemias:from mouse models to clinical applications. Oncogene. Prepublished on July 7,2008, as doi:10.1038/onc.2008.196. This is a comprehensive review of secondary genetic alterations in CBF AML with both t(8;21)and inv(16).
3. Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004:80-97.
4. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferaserelated catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991; 11 (4):2057-65.
5. Harpur AG, Andres AC, Ziemiecki A, Aston RR, Wilks AF. JAK2, a thirdmember of the JAK family of protein tyrosine kinases. Oncogene 1992;7(7):1347-53.
6. Lindauer K, Loerting T, Liedl KR, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng 2001;14(1):27-37.
7. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology:role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol.2008 Aug;19(4):385-93.
8. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006;355(23):2452-66.
9. Dohner K, Du J, Corbacioglu A, Scholl C, Schlenk RF, Dohner H. JAK2V617F mutations as cooperative genetic lesions in t(8;21)-positive acute myeloid leukemia. Haematologica.2006 Nov;91(11):1569-70.
10. 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;106:3370-3.
11. Levine RL, LoriauxM, Huntly BJ, LohML, BeranM, Stoffregen 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; 106:3377-9.
12. Frohling S, Lipka DB, Kayser S, Scholl C, Schlenk RF, Dohner H, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood 2006;107:1242-3.
13. Brasel K, Escobar S, Anderberg R, et al. Expression of the fit3 receptor and its ligand on hematopoietic cells. Leukemia,1995,9 (7):1212～1218.
14. Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia,1996,10 (4):588～599.
15. Drexler HG, Meyer C, Quentmeier H. Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. Leuk Lymphoma,1999,33 (12):83～91.
16. Steudel C, Wermke M, Schaich M, et al. Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer,2003,37:237-251.
17. Moreno I, Martin G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia.Haematologica,2003,88 (1):19～24.
18. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood,2001,97 (8):2434～2439.
19. Edling CE, Hallberg B. c-Kit—a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol.2007;39:1995-1998.
20. Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit:a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J. 1987;6:3341-3351.
21. Blechman JM, Lev S, Barg J, et al. The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. Cell. 1995;80:103-113.
22. Roskoski R Jr. Structure and regulation of Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun.2005;338:1307-1315.
23. Roskoski R Jr. Signaling by Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun.2005;337:1-13.
24. Zhang Z, Zhang R, Joachimiak A, et al. Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Proc Natl Acad Sci USA.2000;97:7732-7737.
25. Cotta CV, Tubbs RR. Mutations in myeloid neoplasms. Diagn Mol Pathol.2008 Dec;17(4):191-9.
26. Orfao A, Garcia-Montero AC, Sanchez L, et al. Recent advances in the understanding of mastocytosis:the role of KIT mutations. Br J Haematol. 2007;138:12-30.
27. Delhommeau F, Dupont S, James C, Masse A, le Couedic JP, Valle VD et al. TET2 is a novel tumor suppressor gene inactivated in myeloproliferative neoplasms: identification of a Pre-JAK2 V617F event. ASH Annual Meeting Abstracts 2008; 112:lba-3. Late-Breaking Abstract.
28. Tefferi A, Pardanani A, Lim K-H, Abdel-Wahab O, Lasho TL, Patel J et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia.2009 May;23(5):905-11.
29. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet.2009 Jul;41(7):838-42.
30. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms:CMML, MDS, MDS/MPN and AML. Leukemia.2009 Jul;23(7):1343-5.
31. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood.2009 Jul 2;114(1):144-7.
32. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, Score J, Seear R, Chase AJ, Grand FH, White H, Zoi C, Loukopoulos D, Terpos E, Vervessou EC, Schultheis B, Emig M, Ernst T, Lengfelder E, Hehlmann R, Hochhaus A, Oscier D, Silver RT, Reiter A, Cross NC. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood.2005 Sep 15;106(6):2162-8. Epub 2005 May 26.
33.王莉红 周春林 张新伟 陈森 王敏 王建祥.FLT3基因内部串联重复突变与急性白血病的关系及临床意义[J].中华血液学杂志,2004,25：393,396
34. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289-301.
35. Yue-Ying Wang, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec. PNAS.2005;102:1104-1109.
36. Wadleigh M, DeAngelo DJ, Griffin JD, Stone RM. After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies. Blood. 2005;105:22-30.
31. Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, Hines R, Akashi K, Zhang DE. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci U S A.2004 Dec 7;101(49):17186-91.
32.王敏,王玲,郝长来,等.ETO转录抑制结构域的分析与鉴定.中华血液学杂志,2003,24：10-13.
33. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen IM, Chen Z, Rowley JD, Willman CL, Zhang DE. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med.2006 Aug;12(8):945-9.
34. Peterson LF, Boyapati A, Ahn EY, et al. Acute myeloid leukemia with the 8q22;21q22 translocation:secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110:799-805.This is a comprehensive review of secondary genetic alterations in CBF AML with t(8;21).
35. Mu" Her AMS, Duque J, Shizuru JA, Lu" bbert M. Complementing mutations in core binding factor leukemias:from mouse models to clinical applications. Oncogene. Prepublished on July 7,2008, as doi:10.103.8/onc.2008.196. This is a comprehensive review of secondary genetic alterations in CBF AML with both t(8;21)and inv(16).
36. Jiao B, Wu CF, Liang Y, Chen HM, Xiong SM, Chen B, Shi JY, Wang YY, Wang JH, Chen Y, Li JM, Gu LJ, Tang JY, Shen ZX, Gu BW, Zhao WL, Chen Z, Chen SJ. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia.2009 Sep;23(9):1598-604.
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2. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based metaanalysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia:a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22:3741-3750.
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14. Schoch C, Haase D, Haferlach T, et al. Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22):an additional deletion in 9q is an adverse prognostic factor. Leukemia.1996;10:1288-1295.
15. Peterson LF, Boyapati A, Ahn EY, et al. Acute myeloid leukemia with the 8q22;21q22 translocation:secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110:799-805.This is a comprehensive review of secondary genetic alterations in CBF AML with t(8;21).
16. Mu" ller AMS, Duque J, Shizuru JA, Lu" bbert M. Complementing mutations in core binding factor leukemias:from mouse models to clinical applications. Oncogene. Prepublished on July 7,2008, as doi:10.1038/onc.2008.196. This is a comprehensive review of secondary genetic alterations in CBF AML with both t(8;21)and inv(16).
17. Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004:80-97.
18. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zurcher G, Ziemiecki A. Two novel protein-tyrosine kinases, each with a second phosphotransferaserelated catalytic domain, define a new class of protein kinase. Mol Cell Biol 1991;11(4):2057-65.
19. Harpur AG, Andres AC, Ziemiecki A, Aston RR, Wilks AF. JAK2, a thirdmember of the JAK family of protein tyrosine kinases. Oncogene 1992;7(7):1347-53.
20. Lindauer K, Loerting T, Liedl KR, Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. Protein Eng 2001; 14(1):27-37.
21. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006;355(23):2452-66.
22. Dohner K, Du J, Corbacioglu A, Scholl C, Schlenk RF, Dohner H. JAK2V617F mutations as cooperative genetic lesions in t(8;21)-positive acute myeloid leukemia. Haematologica.2006 Nov;91(11):1569-70.
23. 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;106:3370-3.
24. Levine RL, LoriauxM, Huntly BJ, LohML, BeranM, Stoffregen 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; 106:3377-9.
25. Frohling S, Lipka DB, Kayser S, Scholl C, Schlenk RF, Dohner H, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood 2006;107:1242-3.
26. Brasel K, Escobar S, Anderberg R, et al. Expression of the fit3 receptor and its ligand on hematopoietic cells. Leukemia,1995,9 (7):1212～1218.
27. Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia,1996,10 (4):588～599.
28. Drexler HG, Meyer C, Quentmeier H. Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. Leuk Lymphoma,1999,33(12):83～91.
29. Steudel C, Wermke M, Schaich M, et al. Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer,2003,37:237-251.
30. Moreno I, Martin G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia.Haematologica,2003,88 (1):19～24.
31. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood,2001,97 (8):2434～2439.
32. Edling CE, Hallberg B. c-Kit—a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol.2007;39:1995-1998.
33. Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit:a new cell surface receptor tyrosine kinase for an unidentified ligand. Embo J. 1987;6:3341-3351.
34. Blechman JM, Lev S, Barg J, et al. The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. Cell. 1995;80:103-113.
35. Roskoski R Jr. Structure and regulation of Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun.2005;338:1307-1315.
36. Roskoski R Jr. Signaling by Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem Biophys Res Commun.2005;337:1-13.
37. Zhang Z, Zhang R, Joachimiak A, et al. Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Proc Natl Acad Sci USA.2000;97:7732-7737.
38. Cotta CV, Tubbs RR. Mutations in myeloid neoplasms. Diagn Mol Pathol.2008 Dec;17(4):191-9.
39. Orfao A, Garcia-Montero AC, Sanchez L, et al. Recent advances in the understanding of mastocytosis:the role of KIT mutations. Br J Haematol. 2007;138:12-30.
40. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006; 20:965-970.
41. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias:an Italian retrospective study. Blood 2006; 107:3463-3468.
42. Shih L-Y, Liang D-C, Huang C-F, et al. Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia 2008; 22:303-307.
43. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21):a Cancer and Leukemia Group B Study. J Clin Oncol.2006;24:3904-3911.
44. Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K. KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood. 2005 Apr 15;105(8):3319-21.
45. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AMLl-ETOpositive AML are associated with impaired event-free and overall survival. Blood 2006; 107:1791-1799.
46. Delhommeau F, Dupont S, James C, Masse A, le Couedic JP, Valle VD et al. TET2 is a novel tumor suppressor gene inactivated in myeloproliferative neoplasms: identification of a Pre-JAK2 V617F event. ASH Annual Meeting Abstracts 2008; 112:lba-3. Late-Breaking Abstract.
47. Delhommeau F, Dupont S, James C, Masse A, le Couedic JP, Valle VD et al. TET2 is a novel tumor suppressor gene inactivated in myeloproliferative neoplasms: identification of a Pre-JAK2 V617F event. ASH Annual Meeting Abstracts 2008; 112:1ba-3. Late-Breaking Abstract.
48. Tefferi A, Pardanani A, Lim K-H, Abdel-Wahab O, Lasho TL, Patel J et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia.2009 May;23(5):905-11.
49. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet.2009 Jul;41(7):838-42.
50. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms:CMML, MDS, MDS/MPN and AML. Leukemia.2009 Jul;23(7):1343-5.
51. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood.2009 Jul 2:114(1):144-7.
52. Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, Hines R, Akashi K, Zhang DE. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci U S A.2004 Dec 7;101(49):17186-91.
53.王敏,王玲,郝长来,等.ETO转录抑制结构域的分析与鉴定.中华血液学杂志,2003,24：10-13.
54. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen IM, Chen Z, Rowley JD, Willman CL, Zhang DE. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med.2006 Aug;12(8):945-9.
55. Peterson LF, Boyapati A, Ahn EY, et al. Acute myeloid leukemia with the 8q22;21q22 translocation:secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110:799-805.This is a comprehensive review of secondary genetic alterations in CBF AML with t(8;21).
56. Jiao B, Wu CF, Liang Y, Chen HM, Xiong SM, Chen B, Shi JY, Wang YY, Wang JH, Chen Y, Li JM, Gu LJ, Tang JY, Shen ZX, Gu BW, Zhao WL, Chen Z, Chen SJ. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia. 2009 Sep;23(9):1598-604.
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