The gene mutation profile and prognostic analysis of acute myeloid leukemia with t(16;21)(p11;q22)/FUS∷ERG fusion
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摘要: 目的 旨在探讨携带t(16；21)(p11；q22)/FUS∷ERG融合基因的急性髓系白血病(acute myeloid leukemia，AML)患者的临床生物学及预后特征。方法 回顾性分析2015年12月—2023年8月在河南省人民医院收治的12例t(16；21)(p11；q22)/FUS∷ERG阳性AML患者的临床和实验室数据，并进行文献复习。结果 t(16；21)(p11；q22)/FUS∷ERG阳性AML占同期初诊AML患者的1.28%(12/935)。患者中男9例，女3例；FAB分型为M2型9例，M4/5型3例。7例患者在诊断时骨髓原始细胞可见空泡形成。所有患者的免疫表型均表达CD56和CD123。染色体核型分析均显示t(16;21)易位，其中7例伴有附加染色体异常。FUS∷ERG融合基因均检测阳性，基因突变情况：PTPN11 50.0%(3/6)、NRAS 36.4%(4/11)、BCOR 22.2%(2/9)、RUNX1 18.2%(2/11)、TET2 18.2%(2/11)、WT1 11.1%(1/9)。汇总国内外文献中基因突变信息，突变率最高为PTPN11，占26.7%(12/45)，其次为NRAS，占23.5%(8/34)，其他常见突变基因为TET2、RUNX1、ASXL1、DNMTA、BCOR等。研究中11例患者诱导化疗后完全缓解率为72.7%，复发率为37.5%；3例患者接受了造血干细胞移植(hematopoietic stem cell transplantation，HSCT)，其中2例移植后复发/死亡。11例患者的中位生存期为15个月(95%CI 9.092~20.908)。结论 t(16；21)(p11；q22)/FUS∷ERG阳性AML是一类罕见的具有特定遗传学特征的AML亚型，具有独特的临床生物学和基因表达谱特征，总体预后较差。HSCT效果可能有限，亟需探索新的靶向治疗方法。Abstract: Objective To investigate the clinical, biological, and prognostic features of patients with acute myeloid leukemia(AML) carrying the t(16;21)(p11;q22)/FUS∷ERG fusion gene.Methods We retrospectively analyzed the clinical and laboratory data of 12 patients with t(16;21)(p11;q22)/FUS∷ERG -positive AML treated in Henan Provincial People's Hospital from December 2015 to August 2023, along with a review of the relevant literature.Results t(16;21)(p11;q22)/FUS∷ERG -positive AML constituted 1.28%(12/935) of de novo AML patients during the same period. The cohort included nine males and three females and the FAB classification was M2 in nine cases and M4/5 in three cases. Vacuole formation in bone marrow blasts was observed in seven patients at diagnosis. The immunophenotype of all patients showed expression of CD56 and CD123. Chromosome analysis revealed the t(16;21) translocation, with additional chromosomal abnormalities in seven cases. The FUS∷ERG fusion gene was detected in all cases, with the following mutation rates: PTPN11 50.0%(3/6), NRAS 36.4%(4/11), BCOR 22.2%(2/9), RUNX1 18.2%(2/11), TET2 18.2%(2/11), WT1 11.1%(1/9). Summarizing the gene mutation information in the literature, the highest mutation rate was PTPN11 accounting for 26.7%(12/45), followed by NRAS accounting for 23.5%(8/34), and the other common mutated genes were TET2, RUNX1, ASXL1, DNMTA and BCOR. The complete remission rate after induction chemotherapy was 72.7% in 11 patients in this study, with a relapse rate of 37.5%. Three patients underwent hematopoietic stem cell transplantation(HSCT), with two experiencing post-transplant relapse/death. The median overall survival for the 11 patients was 15 months(95%CI 9.092-20.908).Conclusion AML with the t(16;21)(p11;q22)/FUS∷ERG fusion gene represents a rare subtype distinguished by its unique genetic and clinical phenotypes and is often associated with a poor prognosis. Hematopoietic stem cell transplantation may have limited efficacy, and there is an urgent need to explore new targeted treatment methods.
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Key words:
- leukemia, myeloid, acute /
- FUS∷ERG fusion gene /
- gene fusion /
- prognosis
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表 1 12例t(16；21)(p11；q22)/FUS∷ERG阳性AML的临床生物学特征
临床参数 数值 性别/例(%) 男 9(75.0) 年龄/岁 22.5(2.0~65.0) WBC/(×109/L) 17.1(3.3~32.3) HGB/(g/L) 76(45~115) PLT/(×109/L) 23(1~170) LDH/(U/L) 1 286(895~3 258) 外周血原始细胞比例/% 79.5(35.0~97.0) 骨髓原始细胞比例/% 76.8(44.4~83.8) FAB分型/例(%) M2 9(75.0) M4 2(16.7) M5 1(8.3) 免疫表型/例(%) CD34 12(100.0) CD56 12(100.0) CD123 12(100.0) cCD79a 1(8.3) 细胞遗传学/例(%) 附加染色体 7(58.3) 复杂核型 2(16.7) -7 1(8.3) 2022ELN危险分层/例(%) 预后中等 7(58.3) 预后不良 5(41.7) 诱导化疗后CR率/例(%) 8/11(72.7) allo-HSCT/例(%) 3/11(27.3) 注：CR：完全缓解；allo-HSCT：异基因造血干细胞移植。 
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表 2 影响t(16；21)(p11；q22)/FUS∷ERG阳性AML总生存的单因素分析
临床参数 HR(95%CI) P 性别(男vs女) 0.380(0.017~8.454) 0.351 年龄 0.539(0.690~4.202) 0.486 WBC 0.755(0.090~6.329) 0.744 HGB 1.404(0.171~11.498) 0.747 PLT 0.253(0.035~1.828) 0.134 LDH 1.500(0.203~11.088) 0.642 骨髓原始细胞比例 0.440(0.061~3.180) 0.394 FAB分型(M2 vs M4/5) 5.000(0.087~286.574) 0.083 2022ELN危险分层(高危组vs中危组) 1.034(0.110~9.756) 0.971 复杂核型 0.397(0.056~2.842) 0.252 附加染色体 0.667(0.090~4.928) 0.642 NRAS 1.283(0.114~14.456) 0.808 RUNX1 2.478(0.284~21.603) 0.302 TET2 2.630(0.118~58.457) 0.351 诱导化疗后CR 0.097(0.000 3~27.033) 0.008 allo-HSCT 0.441(0.053~3.700) 0.261 注：年龄、WBC、HGB、PLT、LDH及骨髓原始细胞比例均以中位数为界值进行分组。
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表 3 t(16；21)(p11；q22)/FUS∷ERG阳性AML的基因突变特征
基因突变特征(突变例数/总例数) 文献来源 NRAS(7/21)、PTPN11(5/21)、RUNX1/WT1/ARID1A(2/21)、ASXL1/SETD2/SUZ12(1/21) Lai等[10] DNMT3A/ASXL1/BCOR/RUNX1/ASXL1(1/3) Zerkalenkova等[11] RUNX1(1/3) Jekarl等[8] RUNX1/TET2(1/3) Ismael等[12] PTPN11(4/13)、WT1(2/13)、NRAS/DNMT3A/TET2/c-KIT/MPL/GATA2/BCOR/RUNX1/ CSF3R/ZMYM3/SMC3/DDX41/PDGFRB/CSMD1(1/13) 许小宇[3] TET2(2/20)、WT1(1/20)、PHF6/NOTCH2(1/20) Pan等[13] TET2(4/6)、ASXL1/KIT/RUNX1(1/6) 仵菲斐等[7] PTPN11(3/11)、CRLF2/ASXL1(1/11) 魏海臣[14] TET2(1/2) 裴荣荣等[15] PTPN11(3/6)、NRAS(4/11)、BCOR(2/9)、RUNX1/TET2(2/11)、WT1/NF1(1/9) 本研究
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