53例伴有11q23/MLL重排的急性髓系白血病的常见基因突变

Clinical Significance of Common Gene Mutations in 53 Patients with Acute Myeloid Leukemia Harboring 11q23/MLL Rearrangements

结论:11q23/MLL重排AML基因突变发生率较高,但多为单一突变,其中RAS通路基因突变最常见。该类患者预后不良,各种基因突变并不影响该类患者的总生存期,FLT3突变患者初诊时血红蛋白高于FLT3野生型患者,行造血干细胞移植可使该类患者获得较好预后。摘要目的:了解AML中常见基因突变在11q23/MLL重排的急性髓系白血病中的发生率,探讨伴有基因突变的11q23/MLL重排AML患者的临床特点,评估这些基因突变对该类AML患者的预后影响。方法:53例AML患者的核型均涉及11q23易位,采用FISH和/或多重PCR进行MLL重排检测;采用基因组DNA-PCR技术对该组标本进行AML中11种常见基因突变的检测,这些基因包括:FLT3-ITD、FLT3-TKD、TET2、N-RAS、ASXL1、EZH2、DNMT3、C-Kit、NPM1、WT1、CEBPA等。结果:53例患者均为MLL重排,其中21例(39.6%)同时合并有其它染色体异常,最常见的为+8;23例(43.4%)为突变阳性,均为单一突变。其中N-RAS突变发生率最高,为8例(15.1%),其次为WT1为4例(7.5%)、FLT3-ITD突变3例、ASXL1突变2例,DNMT3A突变2例,EZH2突变1例,c-Kit17突变1例,FLT3-TKD突变1例,FLT3-ITD和TKD双突变1例,而CEBPA、NPM1、C-KIT8、TET2等基因在本组病例中未发现突变。基因突变患者的中位总生存期为8.5个月,未突变患者的中位总生存期为13个月。18例患者行造血干细胞移植,其中位总生存期为22.5个月,仅行化疗患者的OS时间为7.5个月。

Objective:To investigate the clinical significance of AML patients with 11q23/MLL rearrangement,and to evaluate the effect of those mutations on the AML patients.Methods:53 cases involving translocations of chromosome 11q23 were identified by chromosome banding analysis.MLL rearrangements were detected by fluorescence in situ hybridization and/or multiplex nested PCR.The samples were screened for mutations in the candidate genes FLT3-ITD,FLT3-TKD,TET2,N-RAS,ASXLI,EZH2,DNMT3,C-Kit,NPM1,WT1,CEBPA by using genomic DNA-PCR and deepsequencing.Results:21/53 MLL-rearranged AML cases showed at least one additional chromosomal aberrations.The most common additional aberration was+8.Gene mutations were observed in 23 cases(43.4%)and most cases showed singal mutation.N-RAS mutation was more frequent(8 cases,15.1%),followed by WT1 mutation in 4 cases(7.5%),FLT3-ITD mutation in 3 cases,ASXL1 mutation in 2 cases,DNMT3A mutation in 2 cases,EZH2 mutation in 1 case,c-Kit17 mutation in 1 case,FLT3-TKD mutation in 1 case,and FLT3-ITD and TKD mutation coexistent in 1 case.No mutation was detected in CEBPA,NPM1,C-KIT8,TET2.Median OS for gene mutated patients was 8.5 months and 13 months for no mutated patients.Median OS for patients who received hematopoietic stem cell transplantation(HSCT)was 22.5 months and 7.5 months for patients who olny received chemotherapy.Conclusion:A relatively high mutation frequency is observed in AML patients with 11q23/MLL rearrangements and most cases shows single mutation.The RAS signaling pathway alterations are most common.Gene mutation does not affect the OS of these patients,who show poor prognosis.A significantly higher Hb at initial diagnosis in FLT3 mutated patients is significantly higher than that in FLT3 wild-type cases.Patients who underwent HSCT show a better prognosis than those only received chemotherapy.