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急性髓系白血病几种基因突变与预后的关系(下)

字号+ 作者: 刘加军 来源:医脉通血液科 2021-11-02 我要评论

本文重点介绍对有明确证据与AML预后相关的基因及其与预后的关系。

急性髓系白血病(AML)是造血干细胞恶性克隆性疾病。在AML的诊断、治疗以及判断预后的过程中,基因异常是一项重要指标。随着基因检测技术的不断进步,越来越多与AML发生相关的基因被人们发现,并且这些基因在指导预后方面有重要意义。因此本文参照2017年欧洲白血病网(ELN)根据核型及基因异常建立的AML危险度分层体系,重点介绍对有明确证据与AML预后相关的基因及其与预后的关系。在上期文章中,我们对AML 7种基因突变与预后的关系进行了介绍[详情请戳:急性髓系白血病几种基因突变与预后的关系(上)],今天,我们一起来看看另外6种AML基因突变与预后的关系吧!

 

8BCR-ABL1

 

BCR-ABL1阳性(即费城染色体阳性)的AML是一种非常罕见的类型,发生率不足1%[19]。该种类型的AML通常预后不良,2017年ELN指南将其列入高危险度组。其与其他类型的AML治疗方案也有很大不同,通常需要早期应用TKI,有研究显示,早期接受异基因造血干细胞移植能改善预后,经过造血干细胞移植后,患者5年生存率能够达到53.8%,5年复发率为37%,DFS率为44.2%[20]

 

9GATA2, MECOM

GATA2, MECOM由inv(3)(q21q26.2)/t(3;3)(q21;q26.2)产生,在AML中的发生率约为1-2%[21]。其导致AML的机制与干细胞调节因子生态病毒整合位点1(EVI1)基因附近的GATA2增强子重定位导致该基因的过表达相关[22]

 

GATA2, MECOM基因阳性的AML其OS率极低,预后不良。国外的研究显示该类AML患者5年生存率极低(OS:5.7%±3%;EFS:0%;RFS:4.3%±4%)[23]。另有研究表明,即使经过造血干细胞移植,该类患者的1年和4年的OS率也仅为41%和13%[21]

 

10RUNX1

RUNX1(Runt 相关转录因子1)基因位于21q22染色体,有研究显示该基因突变在AML中发生率约为13%[24]

 

RUNX1负责编码CBF(核心结合因子)中的ɑ亚基,而CBF在造血过程中发挥重要作用,因此RUNX1基因突变会导致AML的发生。

 

在AML中,涉及RUNX1的染色体易位包括t(8;21)(q22;q22); RUNX1-RUNX1T1;t(3;21)(q26.2;q22);以及EVI1-RUNX1。其中RUNX1-RUNX1T1融合基因阳性的AML通常预后较好。2017年ELN特别指出如果RUNX1基因突变合并预后良好组的基因突变,则不应划分至预后不良组。

 

有研究显示RUNX1突变患者较非RUNX1突变患者的预后更差,生存率更低。RUNX1突变AML患者的4年估计生存率如下:EFS率为8%,RFS率为26%,OS率为32%。而在正常核型急性髓系白血病(CN-AML)患者中,RUNX1突变相较非RUNX1突变者EFS较差,但RFS和OS没有发现差异,预计4年EFS率为10%[24]。其他相关研究也支持这种观点[25]

 

11ASXL1

ASXL1(附加性梳样1)基因位于染色体20q11,ASXL1基因突变在AML中发生率较高,约为5%-11%[26]

 

研究表明野生型ASXL1在维持正常造血功能中起重要作用。ASXL1缺失导致祖细胞分化受阻,并会导致髓系恶性肿瘤的发展。大多数ASXL1突变是位于最后一个外显子5‘端附近的杂合子移码或无义突变,这种突变一般被认为是功能缺失性突变,然而,也有研究表明ASXL1突变产生的c端截断的ASXL1蛋白能够诱导髓系转化,导致AML的发生[27]

 

ASXL1突变常与预后不良相关。而2017年ELN指南特别指出如果ASXL1基因突变合并预后良好组的基因突变,则不应划分至预后不良组。与野生型ASXL1患者相比,ASXL1突变患者的CR率、EFS率和OS率较低。有研究显示在中度和不良风险AML组中,ASXL1突变患者的OS和DFS比ASXL1野生型患者更短(3年OS率:47.5% vs 60.8%;3年DFS率:28.5% vs 48.9%)。在CN-AML中,ASXL1突变患者和ASXL1野生型患者之间的OS率(47.4% vs 65.2%)和DFS率(21.0% vs 52.1%)均存在差异[28]

 

12TP53

TP53基因位于17号染色体,虽然TP53基因突变在实体肿瘤中发生率较高,然而在AML中其发生率并不高,约为12.7%[29]

 

在AML中,TP53基因突变会影响p53蛋白质的结构、折叠和稳定性,影响其DNA结合能力和生理活性。其中某些TP53突变可能对剩余的野生型等位基因产生功能丧失(LOF)和显性负效应,而其他突变会导致功能表型的获得,导致肿瘤的形成。

 

在AML中,TP53基因突变通常与预后不良相关,有研究显示TP53基因突变的AML中位OS时间仅有9个月[30]。其他研究也显示,TP53改变与较低的生存率相关。TP53改变和TP53未改变患者的3年估计生存率分别为:EFS率:1% vs 13%;RFS率:7% vs 30%;OS率:3% vs 28%[31]

 

13FLT3-ITD

FLT3(FMS样酪氨酸激酶3基因)属于第Ⅲ类酪氨酸激酶受体家族成员,位于13q12染色体,编码膜结合蛋白。当配体与FLT3受体在胞外结构域结合后,FLT3二聚体化,从而介导一系列细胞内信号传导,调节细胞分化、增殖和凋亡。FLT3基因突变是AML中常见突变,包括近膜区的内部串联重复(internal tandem duplication,ITD)。在AML中FLT3-ITD发生率为约为27%[32]

 

FLT3-ITD突变阳性的AML患者具有易复发、生存期短的特点。有研究显示,根据单因素分析,在比较5年OS率、DFS率、EFS率及缓解率时,FLT3-ITD突变阳性的AML患者较FLT3-ITD突变阴性者较差。国内也有研究显示,FLT3-ITD突变数量不影响患者预后。FLT3-ITD突变重排碱基长度亦对患者预后无明显影响。FLT3-ITD突变比例<10%患者的OS和完全缓解持续时间(CRD)与同期C-KIT突变的中危组AML患者相似,均显著长于突变比例≥10%患者。表明FLT3-ITD突变阳性的AML(除外M3)患者中,FLT3-ITD突变比例<10%的患者预后好于突变比例≥10%的患者[33]

 

总结

综上所述,基因改变与AML预后密切相关,如RUNX1-RUNX1T1融合基因、CBFB-MYH11融合基因、NPM1突变且FLT3突变阴性、CEBPA双突变预后良好;FLT3-ITD突变、ASXL1基因突变、RUNX1基因突变、DEK-NUP214融合基因、GATA2, MECOM预后较差;MLLT3-KMT2A融合基因以及NPM1基因突变合并FLT3-ITD高表达者介于中间。随着检测技术的进步,相信在将来还会有更多与AML发生的相关的基因会被发现,评估这些基因对预后的影响对指导AML的治疗仍有重要意义。

 

参考文献:

[1]OPATZ S, BAMOPOULOS S A, METZELER K H, et al. 2020. The clinical mutatome of core binding factor leukemia. Leukemia [J], 34: 1553-1562.

[2]GAIDZIK V I, BULLINGER L, SCHLENK R F, et al. 2011. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol [J], 29: 1364-1372.

[3]E M Heath,S M Chan,M D Minden,T Murphy,L I Shlush,A D Schimmer. Biological and clinical consequences of NPM1 mutations in AML[J]. Leukemia,2017,31(20):

[4]DUPLOYEZ N, WILLEKENS C, MARCEAU-RENAUT A, et al. 2015. Prognosis and monitoring of core-binding factor acute myeloid leukemia: current and emerging factors. Expert Rev Hematol [J], 8: 43-56.

[5]DOHNER H, ESTEY E, GRIMWADE D, et al. 2017. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood [J], 129: 424-447.

[6]张梦娜,杨艳丽,耿英华,李骏,冯会欣.CEBPA基因突变与急性髓系白血病临床特点及预后关系[J].临床血液学杂志,2021,34(09):659-663.

[7] Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405.[J]. Blood,2016,128(3):

[8] Diagnostic Tool for the Identification of MLL Rearrangements Including Unknown Partner Genes[J]. Proceedings of the National Academy of Sciences of the United States of America,2005,102(2):

[9]C Meyer,E Kowarz,J Hofmann,A Renneville,J Zuna,J Trka,R Ben Abdelali,E Macintyre,E De Braekeleer,M De Braekeleer,E Delabesse,M P de Oliveira,H Cavé, et al New insights to the MLL recombinome of acute leukemias[J]. Leukemia,2009,23(8):

[10]De Braekeleer Marc,Morel Frédéric,Le Bris Marie-Josée,Herry Angèle,Douet-Guilbert Nathalie. The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia.[J]. Anticancer research,2005,25(3B):

[11]Schoch Claudia,Schnittger Susanne,Klaus Mirjam,Kern Wolfgang,Hiddemann Wolfgang,Haferlach Torsten. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases[J]. Blood,2003,102(7):

[12]HEATH E M, CHAN S M, MINDEN M D, et al. 2017. Biological and clinical consequences of NPM1 mutations in AML. Leukemia [J], 31: 798-807.

[13]CHANDRA P, LUTHRA R, ZUO Z, et al. 2010. Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases. Am J Clin Pathol [J], 133: 686-693.

[14]Carl Sanden, Malin Ageberg, Jessica Petersson, Andreas Lennartsson, Urban Gullberg. FORCED EXPRESSION OF THE DEK-NUP214 FUSION PROTEIN PROMOTES PROLIFERATION DEPENDENT ON UPREGULATION OF MTOR[J]. Inventi Impact Cancer,2014,2014:

[15]Díaz-Beyá Marina,Labopin Myriam,Maertens Johan,Alijurf Mahmoud,Passweg Jakob,Dietrich Beelen,Schouten Harry,Socié Gerard,Schaap Nicolaas,Schwerdtfeger Rainer,Volin Liisa,Michallet Mauricette,Polge Emmanuelle,Sierra Jorge,Mohty Mohamad,Esteve Jordi,Nagler Arnon. Allogeneic stem cell transplantation in AML with t(6;9)(p23;q34);DEK-NUP214 shows a favourable outcome when performed in first complete remission.[J]. British journal of haematology,2020,189(5):

[16]BILL M, MROZEK K, KOHLSCHMIDT J, et al. 2020. Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A. Proc Natl Acad Sci U S A [J], 117: 26340-26346.

[17]Y Chen,H Kantarjian,S Pierce,S Faderl,S O'Brien,W Qiao,L Abruzzo,M de Lima,P Kebriaei,E Jabbour,N Daver,T Kadia,Z Estrov,G Garcia-Manero,J Cortes,F Ravandi. Prognostic significance of 11q23 aberrations in adult acute myeloid leukemia and the role of allogeneic stem cell transplantation[J]. Leukemia,2013,27(4):

[18]ASADA S, FUJINO T, GOYAMA S, et al. 2019. The role of ASXL1 in hematopoiesis and myeloid malignancies. Cell Mol Life Sci [J], 76: 2511-2523.

[19]Arber Daniel A.,Orazi Attilio,Hasserjian Robert,Thiele Jürgen,Borowitz Michael J.,Le Beau Michelle M.,Bloomfield Clara D.,Cazzola Mario,Vardiman James W.. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J]. Blood,2016,127(20):

[20]LAZAREVIC V L, LABOPIN M, DEPEI W, et al. 2018. Relatively favorable outcome after allogeneic stem cell transplantation for BCR-ABL1-positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT). Am J Hematol [J], 93: 31-39.

[21]Marta Sitges,Blanca Boluda,Ana Garrido,Mireia Morgades,Isabel et al. Acute myeloid leukemia with inv(3)(q21.3q26.2)/t(3;3)(q21.3;q26.2): Study of 61 patients treated with intensive protocols[J]. European Journal of Haematology,2020,105(2):

[22]Hiromi Yamazaki,Mikiko Suzuki,Akihito Otsuki,Ritsuko Shimizu,Emery H. Bresnick,James Douglas Engel,Masayuki Yamamoto. A Remote GATA2 Hematopoietic Enhancer Drives Leukemogenesis in inv(3)(q21;q26) by Activating EVI1 Expression[J]. Cancer Cell,2014,25(4):

[23]Lugthart Sanne,Gröschel Stefan,Beverloo H Berna,Kayser Sabine, et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.[J]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology,2010,28(24):

[24]Tang Jih Luh,Hou Hsin An,Chen Chien Yuan,Liu Chieh Yu et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations[J]. Blood,2009,114(26):

[25]Gaidzik Verena I,Bullinger Lars,Schlenk Richard F, et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group.[J]. Journal of clinical oncology : official journal of the American Society of Clinical Oncology,2011,29(10):

[26]Chou Wen Chien,Huang Huai Hsuan,Hou Hsin An,Chen Chien Yuan,Tang Jih Luh,Yao Ming,Tsay Woei,Ko Bor Sheng,Wu Shang Ju,Huang Shang Yi,Hsu Szu Chun,Chen Yao Chang,Huang Yen Ning,Chang Yi Chang,Lee Fen Yu,Liu Min Chih,Liu Chia Wen,Tseng Mei Hsuan,Tien Hwei Fang. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations[J]. Blood,2010,116(20):

[27]Shuhei Asada,Takeshi Fujino,Susumu Goyama,Toshio Kitamura. The role of ASXL1 in hematopoiesis and myeloid malignancies[J]. Cellular and Molecular Life Sciences,2019,76(13):

[28]Lin Yun,Wang Yaping,Zheng Yi,Wang Zechuan,Wang Yanni,Wang Shaoyuan. Clinical characteristics and prognostic study of adult acute myeloid leukemia patients with ASXL1 mutations.[J]. Hematology (Amsterdam, Netherlands),2020,25(1):

[29]Magali Olivier,Monica Hollstein,Pierre Hainaut. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use[J]. Cold Spring Harbor Laboratory Press,2010,2(1):

[30]Rücker Frank G.,Schlenk Richard F.,Bullinger Lars,Kayser Sabine,Teleanu Veronica,Kett Helena,Habdank Marianne,Kugler Carla Maria,Holzmann Karlheinz,Gaidzik Verena I.,Paschka Peter,Held Gerhard,von Lilienfeld Toal Marie,Lübbert Michael,Fröhling Stefan,Zenz Thorsten,Krauter Jürgen,Schlegelberger Brigitte,Döhner Hartmut. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome[J]. Blood,2012,119(9):

[31]A Stengel,W Kern,T Haferlach,M Meggendorfer,A Fasan,C Haferlach. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases[J]. Leukemia,2017,31(3):

[32]Kottaridis P D,Gale R E,Frew M E,Harrison G,Langabeer S E,Belton A A,Walker H,Wheatley K,Bowen D T,Burnett A K,Goldstone A H,Linch D C. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.[J]. Blood,2001,98(6):

[33]丁莎莎,沈宏杰,陈子兴,陈苏宁,岑建农,丁子轩,何军.FLT3-ITD突变数量、长度及水平对急性髓系白血病患者预后的影响[J].中华血液学杂志,2015,36(06):449-454.

 

 
 
 
 
 
 

刘加军 教授

  • 教授、主任医师、博士生导师

  • 中山大学附属第三医院血液内科主任

  • 欧洲肿瘤协会抗癌分会会员

  • 中国免疫协会会员

  • 广东省医疗行业协会常委

  • 广东省血液学会会员等

  • 主研方向:白血病细胞凋亡信号转导机制、造血干细胞移植、血液肿瘤的分子靶向治疗、基因治疗及新型抗肿瘤药物的机制研究等。

  • 医疗专长:从事内科血液学临床医疗工作20多年。多年来从事白血病细胞凋亡信号转导机制及血液肿瘤的分子靶向治疗研究。对各种贫血、出血性疾病及血液肿瘤有熟练的诊治能力。诊疗疾病包括血液病造血干细胞移植、白血病化疗、恶性淋巴瘤和多发性骨髓瘤等恶性血液疾病的个体化治疗方案选择、各种原因不明的贫血、不明原因的长期发热以及淋巴结肿大的鉴别诊断和治疗等。

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