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中国生物工程杂志

China Biotechnology
China Biotechnology  2019, Vol. 39 Issue (9): 11-18    DOI: 10.13523/j.cb.20190902
Orginal Article     
Characteristics and Prognostic Significance of Ki-67 Expression at diagnosis in Adult t(8;21) Acute Myeloid Leukemia
DAO Feng-ting,YANG Lu,WANG Ya-zhe,CHANG Yan,YUAN Xiao-ying,LI Ling-di,CHEN Wen-min,LONG Ling-yu,LIU Yan-rong,QIN Ya-zhen()
Peking University Peoples’ Hospital, Peking University Institute of Hematology,National Clinical Research Center for Hematologic Disease, Beijing China,100044
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Abstract  

Objective: To investigate the characteristics and prognostic significance of Ki-67 antigen expression at diagnosis in adult t(8;21) acute myeloid leukemia (AML).Methods: Bone marrow samples of 57 adult t(8;21) AML patients were collected at diagnosis from July 2012 to February 2019 in our hospital, their frequencies of Ki-67 in CD34 + cells were detected by flow cytometry method, and the relationships between Ki-67 and the biological characteristics, therapeutic effect and relapse were analyzed. Results: Of all patients tested, the median percentage of CD34 +Ki-67 + cells were 30.5% (range: 10.0%~65.8%); A receiver operating characteristic (ROC) curve was used to identify the optimal cutoff levels of CD34 +Ki-67 + cells, higher frequencies of CD34 +Ki-67 + cells were significantly related to higher rate of c-KIT mutation and lower WT1 transcript level at diagnosis (P=0.001; P=0.042). Of all patients followed up, higher frequency of CD34 +Ki-67 + cells was significantly related to a higher 1-year cumulative incidence relapse (CIR) rate (P=0.035). In addition, both lower WT1 transcript level at diagnosis and higher level of minimal residual diseases (MRD, < 3-log reduction of the RUNX1-RUNX1T1 transcript level after the second consolidation therapy) were significantly related to a higher 1-year CIR rate (P<0.000 1; P=0.041), and patients with c-KIT mutation and white blood cell count>10×10 9/L at diagnosis tended to have higher 1-year CIR rates, respectively (P=0.091; P=0.054). Patients simultaneously with high frequency of CD34 +Ki-67 + cells and high MRD levels have a significantly higher 1-year CIR rate than others (P<0.000 1). Conclusion: In adult patients with t(8;21) AML, high frequency of CD34 +Ki-67 + cells at diagnosis may be a poor prognostic factor, combination of MRD levels and frequency of CD34 +Ki-67 + cells at diagnosis may better predict relapse than MRD alone.



Key wordsKi-67 antigen      t(8;21) AML      Proto-oncogene proteins c-KIT      WT1      Minimal residual diseases     
Received: 22 August 2019      Published: 20 September 2019
ZTFLH:  Q25  
Corresponding Authors: Ya-zhen QIN     E-mail: qin2000@aliyun.com
Cite this article:

DAO Feng-ting,YANG Lu,WANG Ya-zhe,CHANG Yan,YUAN Xiao-ying,LI Ling-di,CHEN Wen-min,LONG Ling-yu,LIU Yan-rong,QIN Ya-zhen. Characteristics and Prognostic Significance of Ki-67 Expression at diagnosis in Adult t(8;21) Acute Myeloid Leukemia. China Biotechnology, 2019, 39(9): 11-18.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.20190902     OR     https://manu60.magtech.com.cn/biotech/Y2019/V39/I9/11

Fig.1 Gating strategy (a) blast cells in Lin- cells (b) CD34+cells within blast cells (c) isotype control of Ki-67+ cells (d) Ki-67+ cells in CD34+ cells
参数 H-CD34+Ki-67+(n=35) L-CD34+Ki-67+(n=22) P
年龄
≤ 40 岁 16 14 0.28
> 40 岁 19 8
性别
16 14 0.28
19 8
白细胞计数
≤ 10×109/L 21 12 0.58
> 10×109/L 12 10
血红蛋白
≤80 g/L 18 14 0.58
>80 g/L 15 8
血小板
≤ 35×109/L 20 14 1.0
> 35×109/L 13 8
t(8;21)之外的其它异常核型(n=35)
10 10 0.089
12 3
c-KIT基因突变
阳性 24 5 0.001
阴性 11 17
WT1转录本水平
L-WT1 14 3 0.042
H-WT1 21 19
Table 1 The relationship between the percentage of CD34+Ki-67+ cells and Characteristics of the patients at diagnosis
Fig.2 The impact of the percentage of CD34+Ki-67+ cells, the MRD level and the combination of both on 1-year CIR rate (a) H-CD34+Ki-67+ vs L-CD34+Ki-67+ (b) H-MRD vs L-MRD (c) H-CD34+Ki-67+/H-MRD vs Others
[1]   Byrd J C, Mrozek K, Dodge R K , et al. Cancer and leukemia Group B(CALGB 8461). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B(CALGB 8461). Blood, 2002,100(13):4325-4336.
[2]   Schlenk R F, Benner A, Krauter J , et al. Individual patient data-based meta-analysis 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(18):3741-3750.
[3]   Marcucci G, Mrózek K, Ruppert A S , 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(24):5705-5717.
[4]   Schnittger S, Kohl T M, Haferlach T , et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood, 2006,107(5):1791-1799.
[5]   Wang Y Y, Zhou G B, Yin T , et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA, 2005,102(4):1104-1109.
[6]   Qin Y Z, Zhu H H, Jiang Q , et al. Heterogeneous prognosis among KIT mutation types in adult acute myeloid leukemia patients with t(8;21). Blood Cancer J, 2018,8(8):76.
[7]   Qin Y Z, Wang Y, Zhu H H , et al. Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation. Chin J Cancer, 2016,35:46.
[8]   Jourdan E, Boissel N, Chevret S , et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood, 2013,121(12):2213-2223.
doi: 10.1182/blood-2012-10-462879
[9]   Zhu H H, Zhang X H, Qin Y Z , et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission; results from the AML05 multicenter trial. Blood, 2013,121(20):4056-4062.
doi: 10.1182/blood-2012-11-468348
[10]   Shevra C R, Ghosh A, Kumar M . Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium. J Postgrad Med, 2015,61(1):15-20.
[11]   Zheng J N, Pei D S, Mao L J , et al. Inhibition of renal cancer cell growth in vitro and in vivo with oncolytic adenovirus armed short hairpin RNA targeting Ki-67 encoding mRNA. Cancer Gene Ther, 2009,16(1):20-32.
[12]   He X, Chen Z, Fu T , et al. Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis. BMC Cancer, 2014,14:153.
[13]   Vose J M . Mantle cell lymphoma: 2013 update on diagnosis, risk-stratification, and clinical management. Am J Hematol, 2013,88(12):1082-1088.
[14]   Xu P, Yu D, Wang L , et al. Analysis of prognostic factors and comparison of prognostic scores in peripheral T cell lymphoma, not otherwise specified: a single——institution study of 105 Chinese patients. Ann Hematol, 2015,94(2):239-247.
[15]   Shome D K, Khurana N . Distinctive AgNOR patterns of myeloid and lymphoid blasts in acute leukemia. Am J Hematol, 1999,61(2):149-152.
[16]   王喜安, 金冠球, 肖正达 , 等. 白血病细胞Ki-67表达和Ag-NORs计数及其临床意义. 白血病·淋巴瘤, 2001,10(1):22-24.
[16]   Wang X A, Jin G Q, Xiao Z D , et al. Ki-67 expression and Ag-NORs count of leukemia cells and its clinical significance. Leukemia · Lymphoma, 2001,10(1):22-24.
[17]   Sun X, Medeiros L J, Lu D , et al. Dysplasia and high proliferation rate are common in acute myeloid leukemia with inv(16) (p13q22). Am J Clin Pathol, 2003,120(2):236-245.
[18]   Nowicki M, Ostalska-Nowicka D, Miskowiak B . Prognostic significance of Ki67-negative blast cell clone in the high risk group of children treated for acute myeloid leukemia. Folia Histochem Cytobiol, 2006,44(1):49-52.
[19]   Han K, Kahng J, Kim M , et al. Expression of functional markers in acute nonlymphoblastic leukemia. Acta Haematol, 2000,104(4):174-180.
[20]   Kaaijk P, Kaspers G J , Van Wering E R, et al. Cell proliferation is related to in vitro drug resistance in childhood acute leukemia. Br J Cancer, 2003,88(5):775-781.
[21]   施均, 邵宗鸿, 刘鸿 , 等. 骨髓增生异常综合征患者骨髓细胞周期及CD34 +细胞增殖特征的研究 . 中华血液学杂志, 2004,25(11):641-644.
[21]   Shi J, Shao Z H, Liu H , et al. Study on the characteristics of cell cycle and proliferation of CD34 + hematopoietic stem cells in myelodysplastic syndromes . Chinese Journal of Hematology, 2004,25(11):641-644.
[22]   杨文群 . Ki-67、P-gp在急性白血病中的表达及意义. 长沙: 中南大学, 2011.
[22]   Yang W Q . The expression and significance of Ki-67 and P-gp in patients with acute leukemia. Changsha: Central South University, 2011.
[23]   王敏, 王立茹 . Ki-67在急性髓系白血病中的研究进展. 中华实验血液学, 2016,24(4):1264-1268.
[23]   Wang M, Wang L R . Research progress of Ki-67 in acute myeloid leukemia. J Exp Hematol, 2016,24(4):1264-1268.
[24]   Jothilingam P, Basu D, Dutta T K . Angiogenesis and proliferation index in patients with acute leukemia: a prospective study. Bone Marrow Res, 2014,2014:634874.
[25]   Staber P B, Linkesch W, Zauner D , et al. Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia. Oncogene, 2004,23(4):894-904.
[26]   Grimwade D, Walker H, Oliver F , et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 Trial. Blood, 1998,92(7):2322-2333.
[27]   Bloomfield C D, Lawrence D, Byrd J C , et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res, 1998,58(18):4173-4179.
[28]   Besmer P, Murphy J E, George P C , et al. A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature, 1986,320(6061):415-421.
[29]   Furitsu T, Tsujimura T, Tono T , et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest, 1993,92(4):1736-1744.
[30]   Ho P A, Kuhn J, Gerbing R B , et al. WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the children's oncology group. J Clin Oncol, 2011,29(6):704-711.
doi: 10.1200/JCO.2010.31.9327
[31]   Miglino M, Colombo N, Pica G , et al. WT1 overexpression at diagnosis may predict favorable outcome in patients with de novo non-M3 acute myeloid leukemia. Leuk Lymphoma, 2011,52(10):1961-1969.
[32]   Damm F, Heuser M, Morgan M , et al. Integrative prognostic risk score in acute myeloid leukemia with normal karyotype. Blood, 2011,117(17):4561-4568.
doi: 10.1182/blood-2010-08-303479
[33]   Nomdedéu J F, Hoyos M, Carricondo M , et al. Bone marrow WT1 levels at diagnosis, post-induction and postintensification in adult de novo AML. Leukemia, 2013,27(11):2157-2164.
doi: 10.1038/leu.2013.111
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