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中华诊断学电子杂志 ›› 2022, Vol. 10 ›› Issue (03) : 163 -170. doi: 10.3877/cma.j.issn.2095-655X.2022.03.004

基因诊断

RUNX1基因突变对成人急性髓系白血病患者临床特征、疗效及预后的影响
时文霞1, 郭勇鑫2, 申俊杰1, 陈文明3, 郭文文4, 赵同峰4, 赵丹丹4, 陈建4, 孙忠亮4, 孙道萍4,†()   
  1. 1. 272013　济宁医学院临床学院
    2. 271099　泰安，山东第一医科大学（山东省医学科学院）临床学院
    3. 272011　济宁市第一人民医院肿瘤科
    4. 272011　济宁市第一人民医院血液内科
  • 收稿日期:2022-01-23 出版日期:2022-08-26
  • 通信作者: 孙道萍
  • 基金资助:
    山东省自然科学基金(ZR2020MH207); 济宁市科技发展计划项目(济科字[2016]56号-25)

The impact of RUNX1 mutations on clinical characteristics, therapeutic efficacy, and prognosis in adults with acute myeloid leukemia

Wenxia Shi1, Yongxin Guo2, Junjie Shen1, Wenming Chen3, Wenwen Guo4, Tongfeng Zhao4, Dandan Zhao4, Jian Chen4, Zhongliang Sun4, Daoping Sun4,†()   

  1. 1. College of Clinical Medicine, Jining Medical University, Jining 272013, China
    2. College of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271099, China
    3. Department of Oncology, Jining No.1 People′s Hospital, Jining 272011, China
    4. Department of Hematology, Jining No.1 People′s Hospital, Jining 272011, China
  • Received:2022-01-23 Published:2022-08-26
  • Corresponding author: Daoping Sun
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引用本文：

时文霞, 郭勇鑫, 申俊杰, 陈文明, 郭文文, 赵同峰, 赵丹丹, 陈建, 孙忠亮, 孙道萍. RUNX1基因突变对成人急性髓系白血病患者临床特征、疗效及预后的影响[J/OL]. 中华诊断学电子杂志, 2022, 10(03): 163-170.

Wenxia Shi, Yongxin Guo, Junjie Shen, Wenming Chen, Wenwen Guo, Tongfeng Zhao, Dandan Zhao, Jian Chen, Zhongliang Sun, Daoping Sun. The impact of RUNX1 mutations on clinical characteristics, therapeutic efficacy, and prognosis in adults with acute myeloid leukemia[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2022, 10(03): 163-170.

目的

探讨Runt相关转录因子1(RUNX1)基因对成人急性髓系白血病(AML)患者临床特征、疗效及预后的影响。

方法

利用二代测序方法检测2017年4月至2021年10月于济宁市第一人民医院血液内科就诊的145例初诊AML患者中RUNX1、FLT3、NPM1等在内的25种AML相关基因突变情况，按照有无RUNX1基因突变将患者分为RUNX1基因突变(RUNX1mut)组及RUNX1基因野生型(RUNX1wt)组，比较两组在年龄、性别、初诊时外周血细胞计数、骨髓原始细胞比例、FAB分型、细胞遗传学分层、AML细胞免疫表型、伴发基因突变、治疗疗效及生存期方面的差异。

结果

15例(10.34%)患者中检出RUNX1突变。与RUNX1wt组(n＝130)患者相比，RUNX1mut组(n＝15)患者的年龄更大[(61.00±10.42)岁，(49.92±16.33)岁](t＝3.63，P＝0.001)，骨髓原始细胞比例更低[34.01(22.60，45.00)%，55.91(33.44，77.95)%，U＝827.00，P＝0.013]，AML细胞表达CD15[0%(0/15)，26.15%(34/130)，P＝0.022]和CD64[6.67%(1/15)，39.23%(51/130)，χ2＝6.20，P＝0.013]的阳性率更低，合并其他基因突变个数更多[5.00(3.00，6.00)，3.00(2.75，5.00)，U＝650.50，P＝0.032]，且更易伴发EZH2突变[20.00%(3/15)，1.54%(2/130)，P＝0.008]及8号染色体三体(+8)异常[21.43%(3/14)，3.31%(4/121)，P＝0.025]。两组在性别、初诊时外周血细胞计数、FAB分型、细胞遗传学分层及诱导治疗反应率方面均差异无统计学意义(均P>0.05)。另外，RUNX1mut组患者1年总生存期显著低于RUNX1wt组[40.00%(6/15)，66.15%(86/130)，χ2＝3.97，P＝0.046]。

结论

在AML患者中RUNX1基因突变与高龄、低骨髓原始细胞比例、AML细胞低表达CD15和CD64及伴发更多的基因突变相关，RUNX1突变易合并EZH2突变及8号染色体异常。携带有RUNX1突变的患者可能生存期更短，预后更差。

关键词: Runt相关转录因子1, 基因突变, 急性髓系白血病, 临床特征, 预后
Objective

To investigate the effects of Runt-related transcription factor 1 (RUNX1) gene on clinical characteristics, therapeutic efficacy and prognosis in adults with acute myeloid leukemia (AML).

Methods

Using second-generation sequencing technology, 145 newly diagnosed adult AML patients admitted in Department of Hemoatology, Jining No.1 People′s Hospital from April 2017 to October 2021 were found to have 25 AML realted gene mutations, including RUNX1, FLT3, and NPM1. Patients were divided into two groups based on RUNX1 mutation status: RUNX1 mutation (RUNX1mut) and RUNX1 wild type (RUNX1wt). The two groups were compared in terms of age, gender, peripheral blood cell count at initial diagnosis, proportion of bone marrow blasts, FAB typing, cytogenetic stratification, immunotype of AML blasts, co-occurred gene mutation, therapeutic efficiency, and survival.

Results

RUNX1 mutations were found in 15 cases (10.34%). In comparison to the RUNX1wt group (n=130), the patients in the RUNX1mut group (n=15) were older [(61.00±10.42)years old, (49.92±16.33)years old, t=3.63, P=0.001)], bone marrow blasts ratios were lower [34.01(22.60, 45.00)%, 55.91(33.44, 77.95)%, U=827.00, P=0.013], positive rates of CD15 [0%(0/15), 26.15%(34/130), P=0.022] and CD64 [6.67%(1/15), 39.23%(51/130), χ2=6.20, P=0.013] were lower, and the number of mutations associated with other genes were higher [5.00(3.00, 6.00), 3.00(2.75, 5.00), U=650.50, P=0.032]. Furthermore, RUNX1 mutation was more likely to be associated with EZH2 mutation [20.00%(3/15), 1.54%(2/130), P=0.008] and trisomy 8 (+ 8) abnormal karyotype [21.43%(3/14), 3.31%(4/121), P=0.025]. However, there were no significant differences between the two groups in terms of sex, peripheral blood cell count at initial diagnosis, FAB typing, cytogenetic stratification or inductive therapeutic efficiency (all P>0.05). Furthermore, RUNX1mut patients had significantly lower 1-year overall survival than RUNX1wt patients [40.00%(6/15), 66.15%(86/130), χ2=3.97, P=0.046].

Conclusions

RUNX1 mutation is associated with advanced age, lower bone marrow blast ratios, lower expression of CD15 and CD64 on AML blasts, and a higher number of accompanying gene mutations in AML patients. The RUNX1 mutation is more likely to be associated with the EZH2 mutation and the chromosome 8 aberration. Patients with RUNX1 mutations may have a shorter life expectancy and a poor prognosis.

Key words: Runt-related transcription factor 1, Gene mutation, Acute myeloid leukemia, Clinical characteristics, Prognosis
表1 RUNX1基因是否突变的成人急性髓系白血病患者临床特征比较
组别 例数 初诊时年龄(岁，±s) 性别(例) 外周血细胞计数 FAB分型(例，%) 骨髓原始细胞比例[%，M(P25，P75)]
男 女 白细胞(×109)[M(P25，P75)] 血红蛋白(g/L，±s) 血小板(×109)[M(P25，P75)] M1/M2 M4 M5
RUNX1mut组 15 61.00±10.42 8 7 12.20(2.65，26.78) 80.84±22.30 81.00(34.00，115.00) 5(33.33) 0(0) 10(66.67) 34.01(22.60，45.00)
RUNX1wt组 130 49.92±16.33 65 65 10.95(2.87，55.94) 85.57±27.96 46.00(26.00，88.00) 53(40.77) 15(11.54) 62(47.69) 55.91(33.44，77.95)
统计量   t＝3.63 χ2＝0.06 U＝913.00 t＝－0.63 U＝721.00 χ2＝2.89 U＝827.00
P值   0.001 0.807 0.687 0.529 0.099 0.236 0.013
表2 RUNX1基因是否突变的成人急性髓系白血病患者细胞表面抗原表达阳性率比较(例，%)
组别 例数 CD4a CD7 CD9 CD10a CD13 CD15a CD33 CD36 CD34 CD56 CD64 CD123 MPO HLA-DR CD117
RUNX1mut组 15 0(0) 2(13.33) 3(20.00) 1(6.67) 13(86.67) 0(0) 12(80.00) 1(6.67) 12(80.00) 2(13.33) 1(6.67) 9(60.00) 6(40.00) 11(73.33) 13(86.67)
RUNX1wt组 130 19(14.62) 39(30.00) 40(30.77) 1(0.77) 106(81.54) 34(26.15) 120(92.31) 33(25.38) 87(66.92) 29(22.31) 51(39.23) 97(74.62) 70(53.85) 98(75.38) 114(87.69)
χ2值     1.11 0.32   0.02   1.22 1.69 0.54 0.22 6.20 0.81 1.30 0 0
P值   0.220 0.292 0.571 0.197 0.893 0.022 0.270 0.194 0.461 0.638 0.013 0.367 0.309 1.000 1.000
表3 RUNX1基因是否突变的成人急性髓系白血病患者伴发其他基因突变情况比较(例，%)
组别 例数 DNMT3A IDH1/2 EZH2a ASXL1 SF3B1a U2AF1a ZRSR2a SRSF2a JAK1/2/3a CBLa
RUNX1mut组 15 6(40.00) 4(26.67) 3(20.00) 2(13.33) 1(6.67) 1(6.67) 1(6.67) 0(0) 0(0) 1(6.67)
RUNX1wt组 130 29(22.31) 19(14.62) 2(1.54) 10(7.69) 5(3.85) 3(2.31) 3(2.31) 4(3.08) 24(18.46) 6(4.62)
χ2值   1.43 0.70   0.07            
P值   0.231 0.403 0.008 0.798 0.487 0.357 0.357 1.000 0.133 0.542
组别 例数 FLT3 NRAS/KRAS PTPN11 KIT NPM1 TET2 CEBPA WT1 GATA2a TP53a
RUNX1mut组 15 3(20.00) 6(40.00) 1(6.67) 0(0) 1(6.67) 2(13.33) 2(13.33) 2(13.33) 0(0) 1(6.67)
RUNX1wt组 130 41(31.54) 42(32.31) 12(9.23) 16(12.31) 33(25.38) 27(20.77) 21(16.15) 15(11.54) 5(3.85) 5(3.85)
χ2值   0.39 0.10 0   1.69 0.12 0 0    
P值   0.533 0.757 1.000 0.375 0.194 0.733 1.000 1.000 1.000 0.487
表4 RUNX1基因是否突变的成人急性髓系白血病患者伴发细胞遗传学异常比较(例，%)
组别 例数 正常核型 +8a inv(16)a t(8; 21)a t(6; 9)a +11a +21a －7a 9q－a 复杂核型
RUNX1mut组 14 5(35.71) 3(21.43) 0(0) 0(0) 1(7.14) 0(0) 0(0) 1(7.14) 0(0) 2(14.29)
RUNX1wt组 121 58(47.93) 4(3.31) 7(5.79) 12(9.92) 4(3.31) 2(1.65) 1(0.83) 3(2.48) 2(1.65) 13(10.74)
χ2值   0.75                 0
P值   0.386 0.025 1.000 0.613 0.427 1.000 1.000 0.358 1.000 1.000
表5 RUNX1有无突变的成人急性髓系白血病患者诱导治疗疗效的比较(例，%)
组别 化疗 去甲基化药物单药或联合化疗
例数 CR PRa ORR 例数 CRa PRa ORRa
RUNX1mut组 7 3(42.86) 1(14.29) 4(57.14) 6 1(16.67) 2(33.33) 3(50.00)
RUNX1wt组 87 65(74.71) 5(5.75) 70(80.46) 21 12(57.14) 2(9.52) 14(66.67)
χ2值   1.89   0.94        
P值   0.170 0.380 0.332   0.165 0.204 0.638
图1 RUNX1基因有无突变的成人急性髓系白血病患者总生存期的比较注：RUNX1mut为RUNX1基因突变；RUNX1wt为RUNX1基因野生型
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