<i>BCR-FIBCD1-ABL1</i>融合基因阳性的儿童慢性粒细胞白血病一例报道并文献复习

摘要/Abstract

摘要：

目的：分析1例少见型BCR-ABL1融合基因阳性的慢性期慢性粒细胞白血病（chronic myelogenous leukemia, CML）儿童患者的基因表型，评价其经酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）治疗后的疗效，并总结数据库报道的该病以少见型融合基因e8a2BCR-ABL1表型患者的治疗及预后。方法：分析我院收治的1例3岁的慢性期CML患者，同时检索PubMed和万方数据库中报道慢性期CML患者表现为罕见型融合基因e8a2BCR-ABL1的情况。结果：该例患儿因皮肤瘀斑、颈部淋巴结肿大就诊于我院，骨髓细胞形态学示CML慢性期，但外周血及骨髓检查P190、P210、P230均阴性，后经外周血巢式PCR检测发现存在BCR（e8）-FIBCD1-ABL1（a2）融合基因阳性。数据库中已报道的26例e8a2型融合基因阳性的CML病例均为成人，最常见的临床表现为白细胞和血小板计数增多伴脾肿大，并以e8-ABLint1b-a2基因型为主。21例患者接受TKI治疗，其中19例（90.4%）达到不同程度的分子学反应。本例患儿亦是以白细胞升高伴血小板增多起病，在接受伊马替尼治疗后，目前持续达到完全血液学缓解，分子学无法检测到BCR-ABL1融合基因转录本，但随访至39个月时，复查见骨髓染色体呈38~40,XX,-7,-17,-20,-21,-22[cp7] /46,XX复合核型。结论：e8a2BCR-ABL1融合基因突变所致的慢性期CML少见，本文首次报道了1例该融合基因突变所致的儿童慢性期CML病例。该患儿经TKI治疗后持续达到完全血液学缓解，但骨髓染色体发现异常核型，提示临床中该变异基因型可能发生预后不良结局，需继续密切随访患者。

关键词:儿童,慢性粒细胞白血病,e8a2,酪氨酸激酶抑制剂

Abstract:

Objective:To analyze the genetic phenotype of a pediatric chronic phase chronic myeloid leukemia(CML-CP) patient with a rareBCR-ABL1fusion transcript and evaluate the therapeutic effect of tyrosine kinase inhibitor (TKI), also we review the reported cases in the databases to explore the treatment and prognosis in chronic myeloid leukemia withe8a2 BCR-ABL1fusion gene.Methods:A 3-year-old girl was diagnosed with CML-CP in our hospital，the laboratory results and treatment were analyzed. Treatment and response to TKI inhibitors in the CML-CP patients presented with a novel e8a2 fusion gene were reviewed by searching the databases of pubmed and wanfang.Results:The patient was admitted to our hospital due to skin ecchymosis and cervical lymph node swelling，and was diagnosed as CML by bone marrow cell morphology, but P190, P210 and P230 were negative in peripheral blood and bone marrow examination.BCR (e8) -FIBCD1-ABL1 (a2)fusion gene was positive in peripheral blood by Nested RT-PCR. A total of 26 CML patients withe8a2 BCR-ABL1fusion transcript in the database were reviewed, all of which were adult cases. In the literature, 21 patients received TKI inhibitor treatment, 19/21 (90.4%) achieved different degrees of molecular response. This case onset with elevated white blood cells and thrombocytopenia,and after imatinib treatment， the patient had achieved complete hematologic remission, and theBCR-ABL1fusion gene transcript could not be detected. However, the bone marrow chromosomes showed a complex karyotype of 38-40,XX,-7,-17,-20,-21,-22[cp7] /46,XX at the follow-up of 39 months.Conclusions:CMI-CP with e8a2 BCR-ABL1 genotype is rare, we first report this atypicale8a2 BCR-ABL1transcript expression in pediatric CML patient. Although complete hematological remission continued after TKI inhibitor treatment, an abnormal karyotype was found in bone marrow chromosomes, suggesting that this variant genotype may have a poor prognosis, and following up closely is necessary.

Key words:Pediatric,Chronic myeloid leukemia,e8a2,Tyrosine kinase inhibitor

中图分类号:

R733.72
R446

张姣, 闾佳佳, 陆文丽, 张莉丹, 李卫.BCR-FIBCD1-ABL1融合基因阳性的儿童慢性粒细胞白血病一例报道并文献复习[J]. 诊断学理论与实践, 2023, 22(05): 472-479.

ZHANG Jiao, LÜ Jiajia, LU Wenli, ZHANG Lidan, LI Wei. Pediatric chronic myeloid leukemia with aBCR- FIBCD1-ABL1fusion transcript: a case report and literature review[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(05): 472-479.

图/表5

图1

图2

图3A

图4

表1

e8a2 BCL-ABL1融合基因阳性CML患者临床及基因型特征

Case	Age	Sex	Presentation	Genotype	Therapy	Follow-up(month)	Prognosis
1^{[ 5 ]}	51	Male	hepatomegaly thrombocytosis	e8a2	hydroxyurea+αlpha interferon	12	PHR
2^{[ 9 ]}	40	Female	splenomegaly thrombocytosis	e8-ABLint1a- a2	imatinib	65	resistant
3^{[ 10 ]}	46	Male	leukocytosis Splenomegaly	e8-ABLint1a- a2	imatinib	3	MMR
4^{[ 11 ]}	25	Male	anorexia nausea	e8-BCRint8 -a2	dasatinib	3	EMR
5^{[ 12 ]}	51	Female	abdominal pain	e8-MAST2e2 -a2	imatinib	16	MMR
6^{[ 13 ]}	40	Male	leukocytosis	e8-ABLint1b -a2	imatinib	33	MMR
7^{[ 13 ]}	35	Male	leukocytosis	e8-ABLint1b -a2	imatinib	30	MMR
8^{[ 13 ]}	47	Male	leukocytosis	e8-ABLint1b -a2	imatinib	39	MMR
9-13^{[ 14 ]}	--	--	--	e8-ABLint1b -a2	imatinib	--	MMR
14^{[ 14 ]}	--	--	--	e8-DRG1e4 -a2	imatinib	--	MMR
15^{[ 14 ]}	--	--	--	e8-ABLint1a- a2	imatinib	--	MMR
16^{[ 15 ]}	43	Male	splenomegaly thrombopenia	e8-BCRint8 -a2	imatinib	12	MMR
17^{[ 16 ]}	55	Male	acceleration phase	e8-ABLint1b -a2	αlpha interferon	24	death
18^{[ 17 ]}	49	Male	fatigue、facial and palpebral conjunctiva congestion	e8a2withTP53、CDH10 mutation	dasatinib	6	MMR
19^{[ 18 ]}	67	Male	--	e8-PRDM12e4-a2	nilotinib / imatinib	82	DMR
20^{[ 18 ]}	58	Female	--	e8-SPECC1Le3-a2	imatinib	66	MMR
21^{[ 19 ]}	69	Female	leukocytosis	e8-ABLint1b- a2	hydroxyurea	48	no progression
22^{[ 20 ]}	25	Male	anorexia nausea	e8a2	dasatinib	6	MMR
23^{[ 21 ]}	34	Male	lymphadenopathy splenomegaly leukocytosis	e8a2	imatinib	2	extramedullary blast crisis
24^{[ 22 ]}	70	Male	NA	e8a2	NA	NA	NA
25^{[ 22 ]}	25	Female	NA	e8a2	NA	NA	NA
26^{[ 23 ]}	74	Male	NA	e8-ABLint1b-a2	nilotinib	12	MMR

表1

参考文献29

[1]	QUINTÁS-CARDAMA A, CORTES J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia[J].Blood,2009,113(8):1619-1630. doi:10.1182/blood-2008-03-144790 URL
[2]	BERTORELLE R, BONALDI L, BIANCHINI E, et al. The e19a2BCR/ABLfusion transcript with additional chromosomal aberrations on a new case of chronic mye-loid leukemia (CML) of mild type[J].Leukemia,2001,15(12):2003-2004. doi:10.1038/sj.leu.2402292
[3]	HAYETTE S, TIGAUD I, THOMAS X, et al. Identification of a rare e6a2BCR-ABLfusion gene during the di-sease progression of chronic myelomonocytic leukemia: a case report[J].Leukemia,2004,18(10):1735-1736. doi:10.1038/sj.leu.2403476
[4]	CALLET-BAUCHU E, SALLES G, GAZZO S, et al. Identification of a novel e8/a4BCR/ABLfusion transcript in a case of a transformed Sézary syndrome[J].Haematologica,2007,92(9):1277-1278. doi:10.3324/haematol.11341 URL
[5]	HOW G F, LIM L C, KULKARNI S, et al. Two patients with novelBCR/ABLfusion transcripts (e8/a2 and e13/a2) resulting from translocation breakpoints within BCR exons[J].Br J Haematol,1999,105(2):434-436. doi:10.1111/bjh.1999.105.issue-2 URL
[6]	STELLA S, MASSIMINO M, TIRRÒ E, et al. Detection and clinical implications of a novelBCR-ABL1E12A2 insertion/deletion in a CML patient expressing the E13A2 Isoform[J].Anticancer Res,2019,39(12):6965-6971. doi:10.21873/anticanres.13918 URL
[7]	DUAN M H, LI H, CAI H. A rare e13a3 (b2a3) BCR-ABL1 fusion transcript with normal karyotype in chronic myeloid leukemia: The challenges in diagnosis and monitoring minimal residual disease (MRD)[J].Leuk Res,2017,59:8-11. doi:10.1016/j.leukres.2017.05.009 URL
[8]	GUI X, ZHANG Y, PAN J, et al. Chronic myeloid leukemia with e14a3BCR-ABLtranscript: analysis of characteristics and prognostic significance[J].Leuk Lymphoma,2015,56(12):3343-3347. doi:10.3109/10428194.2015.1037751 URL
[9]	QIN Y Z, JIANG B, JIANG Q, et al. Imatinib mesylate resistance in a chronic myeloid leukemia patient with a novel e8a2BCR-ABLtranscript variant[J].Acta Haematol,2008,120(3):146-149. doi:10.1159/000178145 URL
[10]	PARK I J, LIM Y A, LEE W G, et al. A case of chronic myelogenous leukemia with e8a2 fusion transcript[J].Cancer Genet Cytogenet,2008,185(2):106-108. doi:10.1016/j.cancergencyto.2008.06.001 URL
[11]	CHEN L, WU Y, YOU Y, et al. A novel e8a2BCR-ABL1intronic fusion through insertion of a chromosome 22BCRgene fragment into chromosome 9 in an atypical Philadelphia (Ph) chromosome chronic myeloid leukemia patient[J].Leuk Lymphoma,2016,57(12):2930-2933. doi:10.3109/10428194.2016.1173211 URL
[12]	RIVA E, MANRIQUE ARECHAVALETA G, DE ALMEIDA C, et al. A novel e8a2BCR-ABL1fusion with insertion of MAST2 exon 2 in a four-way translocation t (1;17;9;22) (p35;q24;q44;q11) in a patient with chronic myeloid leukemia[J].Leuk Lymphoma,2016,57(1):203-205. doi:10.3109/10428194.2015.1043549 URL
[13]	CAYUELA J M, ROUSSELOT P, NICOLINI F, et al. Identification of a rare e8a2BCR-ABLfusion gene in three novel chronic myeloid leukemia patients treated with imatinib[J].Leukemia,2005,19(12):2334-2336. doi:10.1038/sj.leu.2403986
[14]	QIN Y Z, JIANG Q, JIANG H, et al. Prevalence and outcomes of uncommonBCR-ABL1fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre[J].Br J Haematol,2018,182(5):693-700. doi:10.1111/bjh.2018.182.issue-5 URL
[15]	TCHIRKOV A, COUDERC J L, PÉRISSEL B, et al. Major molecular response to imatinib in a patient with chronic myeloid leukemia expressing a novel form of e8a2BCR-ABLtranscript[J].Leukemia,2006,20(1):167-168. doi:10.1038/sj.leu.2404012
[16]	BRANFORD S, RUDZKI Z, HUGHES T P. A novelBCR-ABLtranscript (e8a2) with the insertion of an inverted sequence ofABLintron 1b in a patient with Philadelphia-positive chronic myeloid leukaemia[J].Br J Haematol,2000,109(3):635-637. doi:10.1046/j.1365-2141.2000.02042.x URL
[17]	ZHANG Y, CHENG Z, YAN W Z, et al. Molecular characterization and therapeutic reaction to dasatinib in a CML patient harboring a novel e8a2BCR-ABL1transcript with a somatic mutation in TP53BP2 and cadherin-10 genes[J].Leuk Lymphoma,2018,59(1):233-236. doi:10.1080/10428194.2017.1323269 URL
[18]	HUET S, DULUCQ S, CHAUVEAU A, et al. Molecular characterization and follow-up of five CML patients with newBCR-ABL1fusion transcripts[J].Genes Chromosomes Cancer,2015,54(10):595-605. doi:10.1002/gcc.v54.10 URL
[19]	SUGIMOTO T, IJIMA K, HISATOMI H, et al. Second case of CML with aberrantBCR-ABLfusion transcript (e8/a2) with insertion of an invertedABLintron 1b sequence[J].Am J Hematol,2004,77(2):164-166. doi:10.1002/ajh.v77:2 URL
[20]	向航, 吴耀辉, 李小青, 等. 达沙替尼治疗e8a2BCR-ABL1慢性粒细胞白血病1例并文献复习[J].临床血液学杂志,2016,29(5):752-754.
	XIANG H, WU Y H, LI X Q, et al. A case of e8a2BCR-ABL1chronic myeloid leukemia treated with dasatinib and literature review[J].J Clin Hematol,2016,29(5):752-754.
[21]	余铭珊.以淋巴结肿大为首发症状的罕见型BCR/ABL1慢性粒细胞白血病1例并文献复习[D]. 广西: 广西医科大学,2017.
	YU M S.A case of rareBCR/ACL1 chronic myelogenous leukemia with lymphadenopathy as the first symptom and review of the literature[D]. Guangxi: Guangxi Medical University,2017.
[22]	ZOU Y, DU C, CHEN H M, et al. Application of Real-time Quantitative PCR in Detecting AtypicalBCR/ABLmRNA Transcripts in Chronic Myelocytic Leukemia[J].Zhongguo Shi Yan Xue Ye Xue Za Zhi,2017,25(4):1016-1021.
[23]	BURMEISTER T, BULLINGER L, LE COUTRE P. The Recurrent Atypical e8a2BCR::ABL1Transcript with Insertion of an Inverted 55 Base PairABL1Intron 1b Sequence: A Detailed Molecular Analysis[J].Acta Haematol,2023,146(5):413-418. doi:10.1159/000531128 URL
[24]	HIJIYA N, SCHULTZ K R, METZLER M, et al. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach[J].Blood,2016,127(4):392-399. doi:10.1182/blood-2015-06-648667pmid:26511135
[25]	DEMEHRI S, PASCHKA P, SCHULTHEIS B, et al. e8a2BCR-ABL: more frequent than other atypicalBCR-ABLvariants?[J].Leukemia,2005,19(4):681-684. doi:10.1038/sj.leu.2403604
[26]	TANIZAWA A. Optimal management for pediatric chronic myeloid leukemia[J].Pediatr Int,2016,58(3):171-179. doi:10.1111/ped.12876pmid:26646444
[27]	DE LA FUENTE J, BARUCHEL A, BIONDI A, et al. Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years[J].Br J Haematol,2014,167(1):33-47. doi:10.1111/bjh.2014.167.issue-1 URL
[28]	GORE L, KEARNS P R, DE MARTINO M L, et al. Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: results from a phase Ⅱ trial[J].J Clin Oncol,2018,36(13):1330-1338. doi:10.1200/JCO.2017.75.9597 URL
[29]	HIJIYA N, MASCHAN A, RIZZARI C, et al. Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia[J].Blood,2019,134(23):2036-2045. doi:10.1182/blood.2019000069pmid:31511239

BCR-FIBCD1-ABL1融合基因阳性的儿童慢性粒细胞白血病一例报道并文献复习

Pediatric chronic myeloid leukemia with aBCR- FIBCD1-ABL1fusion transcript: a case report and literature review

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表5

参考文献29

相关文章15

编辑推荐

Metrics

本文评价

[1]	张天羽, 周东, 洪桢.《儿童抗NMDAR脑炎治疗的国际共识推荐》解读[J]. 诊断学理论与实践, 2022, 21(06): 677-683.
[2]	沈小钰, 沙莎, 殷蕾, 周纬, 骆凝馨, 王雪峰.儿童原发性肾病综合征动态血压变化特点的临床分析[J]. 诊断学理论与实践, 2022, 21(05): 613-618.
[3]	游碧君, 王金辉, 庄鸿源.儿童输血反应发生率及输血反应原因分析和改进措施探讨[J]. 诊断学理论与实践, 2021, 20(04): 396-398.
[4]	董治亚, 戴彤彤.肠道微生物群与儿童生长间相关性的研究进展及临床意义[J]. 诊断学理论与实践, 2021, 20(03): 234-238.
[5]	韦若蕖, 余红, 姚志荣.儿童成纤维细胞结缔组织痣一例报道并文献复习[J]. 诊断学理论与实践, 2021, 20(02): 190-194.
[6]	匡新宇, 黄文彦.儿童遗传性肾脏病的分类及诊治进展[J]. 诊断学理论与实践, 2021, 20(02): 117-124.
[7]	李松涛, 杨大恒, 孙杭, 岳玉林, 张倩, 刘倩琦, 武苏, 马长艳.甲状腺功能血清学指标结合超声检查在鉴别儿童毒性弥漫性甲状腺肿与慢性淋巴细胞性甲状腺炎中的价值[J]. 诊断学理论与实践, 2020, 19(06): 600-604.
[8]	孟磊俊, 张晶, 王雪莉, 李治, 张泓, 曾乃燕.儿童伯基特淋巴瘤中差异表达基因的鉴定及临床应用[J]. 诊断学理论与实践, 2020, 19(03): 248-257.
[9]	.三维平衡稳态自由进动磁共振成像序列在儿童冠状动脉异常起源于肺动脉诊断中的应用价值[J]. 诊断学理论与实践, 2020, 19(02): 145-150.
[10]	胡立伟, 孙爱敏, 王谦, 郭辰, 欧阳荣珍, 姚小芬, 钟玉敏.心脏磁共振特征追踪成像技术在单心室术后心肌应变力评估中的应用研究[J]. 诊断学理论与实践, 2019, 18(05): 509-514.
[11]	王亚娟, 郭芊卉, 张冬燕, 程艾邦, 陈凌, 朱鼎良, 李燕.上海莘庄社区儿童及青少年超重、肥胖的发生率及血压相关因素分析[J]. 诊断学理论与实践, 2019, 18(05): 575-580.
[12]	严华杰, 范德平, 邵洁.儿童下呼吸道感染两种方法检测肺炎支原体IgM结果差异性分析[J]. 诊断学理论与实践, 2018, 17(05): 572-574.
[13]	谢国艳, 高志生, 秦云, 李星军, 谭永强,.上海崇明地区儿童急性下呼吸道感染的流行特点与临床特征分析[J]. 诊断学理论与实践, 2016, 15(04): 410-414.
[14]	卢水华,.儿童结核病诊治的新认识[J]. 诊断学理论与实践, 2015, 14(05): 397-401.
[15]	刘淑平, 丁洁, 姚勇, 俞礼霞, 王芳,.儿童Gitelman综合征一例并文献复习[J]. 诊断学理论与实践, 2014, 13(05): 524-528.