Clinical and genetic features of 96 children with core binding factor acute myeloid leukemia
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摘要: 目的 分析核心结合因子相关儿童急性髓系白血病(CBF-AML)的临床及遗传学特征。方法 回顾性分析2016年1月—2021年12月于中国医学科学院血液病医院儿童血液病诊疗中心确诊的96例初诊CBF-AML患儿的临床资料。总结并比较RUNX1-RUNX1T1与CBFβ-MYH11两种融合基因型患儿的临床及遗传学特征。结果 96例患儿中，RUNX1-RUNX1T1与CBFβ-MYH11两种融合基因型组病例分别为76例(79.2%)和20例(20.8%)。CBFβ-MYH11组与RUNX1-RUNX1T1组比较，具有更高的初诊白细胞计数(P=0.001)。2组患儿初诊出现白血病髓外浸润比例相当(22.4% vs 20.0%)，但CBFβ-MYH11组髓外浸润部位均为中枢神经系统(20.0%，P=0.033)，RUNX1-RUNX1T1组髓外浸润部位多为眶周及面部软组织(14.5%，P=0.063)。性染色体缺失是儿童CBF-AML中最为常见的附加细胞遗传学异常，总体发生率为34.4%(32/93)，且仅发生在RUNX1-RUNX1T1融合基因阳性的AML中。染色体三体现象常见，+8在CBFβ-MYH11组出现频率更高(15.0%，P=0.03)。CBF-AML患儿常见的伴随突变基因有C-KIT(53.9%)、NRAS(31.6%)、KMT2D(15.8%)、KRAS(13.2%)等。结论 儿童CBF-AML中，CBFβ-MYH11组初诊白细胞水平更高，髓外浸润部位为中枢神经系统。性染色体缺失主要发生在RUNX1-RUNX1T1组，髓外浸润部位常为头面部。C-KIT和RAS突变是CBF-AML中最常见的基因突变类型。Abstract: Objective To analyze the clinical and genetic features of core binding factor acute myeloid leukemia(CBF-AML) in children.Methods A retrospective analysis was performed from the chart review data of children who were newly diagnosed with CBF-AML in the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, from January 2016 to December 2021. The clinical and genetic characteristics of children with two fusion genotypes, RUNX1-RUNX1T1 and CBFβ-MYH11, were summarized and compared.Results Of the 96 children, 76 children(79.2%) and 20 children(20.8%) were in the RUNX1-RUNX1T1 and CBFβ-MYH11 fusion genotype groups, respectively. The CBFβ-MYH11 group had a higher initial white blood cell count compared to the RUNX1-RUNX1T1 group(P=0.001). The proportion of children with extramedullaryleukaemia infiltration at first diagnosis was comparable in both subgroups(22.4% vs 20.0%). However, the site of extramedullary infiltration in the CBFβ-MYH11 group was all in the central nervous system(20.0%, P=0.033), while in the RUNX1-RUNX1T1 group the site of extramedullary infiltration was mostly in the periorbital and facial soft tissues(14.5%, P=0.063). Sex chromosome deletions were the most common additional cytogenetic abnormality in children with CBF-AML, with an overall incidence of 34.4%(32/93) and occurring only in t(8; 21)-AML. Chromosomal trisomies were common, with +8 occurring more frequently in the CBFβ-MYH11 group(15.0%, P=0.03). Common concomitant mutated genes in children with CBF-AML were C-KIT(53.9%), NRAS(31.6%), KMT2D(15.8%) and KRAS(13.2%).Conclusion In pediatric CBF-AML, the CBFβ-MYH11 group had higher initial leukocyte levels and the site of extramedullary infiltration was the central nervous system. The sex chromosome deletion occurs mainly in the RUNX1-RUNX1T1 group and the extramedullary infiltration was often occur in soft tissues of head and face. C-KIT and RAS mutations are the most common types of mutations in CBF-AML.
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Key words:
- core binding factor /
- acute myeloid leukemia /
- children /
- gene mutations
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表 1 CBF-AML患儿基本临床特征
项目 RUNX1-RUNX1T1组(n=76) CBFβ-MYH11组(n=20) χ2/Z P 性别/例(%) 0.462 0.497 男 43(56.6) 13(65.0) 女 33(43.4) 7(35.0) 诊断年龄/岁 8.0(2.0~15.0) 9.0(2.0~13.0) -0.435 0.664 白细胞计数/(×109·L-1) 13.7(1.5~157.0) 40.1(6.4~263.5) -3.365 0.001 血红蛋白/(g·L-1) 82.0(35.0~116.0) 80.0(52.0~112.0) -0.081 0.935 血小板计数/(×109·L-1) 48.5(2.0~239.0) 42.5(10.0~153.0) -0.717 0.473 骨髓原始细胞比例/% 33.4(2.9~92.9) 42.2(11.9~68.3) -1.506 0.132 乳酸脱氢酶/(U·L-1) 484.1(166.5~12 045.0) 479.0(290.0~1 482.0) -0.165 0.869 初诊髓外浸润/例(%) 17a)(22.4) 4(20.0) 0.052 1.000 中枢浸润b) 3(3.9) 4(20.0) 6.036 0.033 头面部软组织浸润c) 11(14.5) 0 3.317 0.063 胸、腰、骶椎浸润d) 4(5.3) 0 1.098 0.577 a)1例患儿同时存在胸、腰椎体及面部软组织浸润；b)中枢浸润包含初诊首次脑脊液流式细胞检测出现异常原始细胞或影像学提示脑实质浸润改变；c)头面部浸润包含眶部绿色瘤或面神经浸润改变；d)胸、腰、骶椎浸润包含局部椎体骨质破坏，累及椎体旁软组织及脊髓。 
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表 2 CBF-AML患儿常见细胞遗传学异常
例(%) 附加染色体异常类型 CBF-AML(n=93) RUNX1-RUNX1T1(n=73) CBFβ-MYH11(n=20) P 性染色体缺失 -X 6(6.5) 6(8.2) 0 0.335 -Y 26(28.0) 26(35.6) 0 0.001 染色体三体 +4 4(4.3) 3(4.1) 1(5.0) 1.000 +8 4(4.3) 1(1.4) 3(15.0) 0.030 +22 5(5.4) 2(2.7) 3(15.0) 0.065 常染色体缺失 -9/9q- 4(4.3) 4(5.5) 0 0.574 复杂核型 6(6.5) 3(4.1) 3(15.0) 0.077
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表 3 CBF-AML患儿分子遗传学异常
突变基因类型 总体分子遗传学异常率/% RUNX1-RUNX1T1异常率/% CBFβ-MYH11异常率/% χ2 P C-KIT 53.9(48/89) 58.6(41/70)a) 36.8(7/19) 2.840 0.077 C-KIT17 41.6(37/89) 48.6(34/70) 15.8(3/19) 6.612 0.010 C-KIT8 12.4(11/89) 10.0(7/70) 21.1(4/19) 1.685 0.239 C-KIT2 1.1(1/89) 1.4(1/70) 0 0.275 1.000 C-KIT9 1.1(1/89) 1.4(1/70) 0 0.275 1.000 C-KIT11 1.1(1/89) 1.4(1/70) 0 0.275 1.000 RASb) N-RAS 31.6(24/76) 23.0(14/61) 66.7(10/15) 10.649 0.002 K-RAS 13.2(10/76) 6.6(4/61) 40.0(6/15) 11.748 0.003 KMT2D 15.8(12/76) 18.0(11/61) 6.7(1/15) 1.170 0.440 FAT1 13.2(10/76) 13.1(8/61) 13.3(2/15) 0.001 1.000 CSF3R 11.8(9/76) 13.1(8/61) 6.7(1/15) 0.479 0.678 CBL 10.5(8/76) 11.5(7/61) 6.7(1/15) 0.296 0.691 FLT3-TKD 10.5(8/76) 9.8(6/61) 13.3(2/15) 0.156 0.653 JAK3 9.2(7/76) 9.8(6/61) 6.7(1/15) 0.145 1.000 CUX1 7.9(6/76) 8.2(5/61) 6.7(1/15) 0.039 1.000 RELN 7.9(6/76) 4.9(3/61) 20.0(3/15) 3.766 0.087 DIS3 6.6(5/76) 4.9(3/61) 13.3(2/15) 1.387 0.254 ASXL2 5.3(4/76) 6.6(4/61) 0 1.813 0.579 ATG2B 5.3(4/76) 6.6(4/61) 0 1.813 0.579 ATM 5.3(4/76) 6.6(4/61) 0 1.813 0.579 BCOR 5.3(4/76) 3.3(2/61) 13.3(2/15) 2.441 0.172 EZH2 5.3(4/76) 6.6(4/61) 0 1.813 0.579 IDH1 5.3(4/76) 6.6(4/61) 0 1.813 0.579 KDM6A 5.3(4/76) 6.6(4/61) 0 1.813 0.579 SETBP1 5.3(4/76) 6.6(4/61) 0 1.813 0.579 a)1例C-KIT 2、C-KIT17双突变, 1例C-KIT8、C-KIT17双突变，1例C-KIT8、C-KIT11双突变; b)6例N-RAS、K-RAS双突变。
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