| Objective: To study the clinical characteristics and prognostic effects of DNMT3 A gene mutation in acute myeloid leukemia（AML）,such as hematology,proportion of bone marrow blasts and molecular genetics.To provide a new basis for improving the prognostic stratification of AML.Methods: A total of 154 patients with newly diagnosed AML（non APL）admitted to the Department of Hematology of the first hospital of Lanzhou University from May 2014 to October 2021 and 40 patients with newly diagnosed to the Department of Hematology of Gansu Provincial Hospital from May 2019 to October2021 were collected.patients were regrouped into DNMT3 A wild type and mutant type according to DNMT3 A gene mutation.Since DNMT3 A mutations are often associated with FLT3-ITD and NPM1 mutations,patients can also be divided into single-mutation group A:（DNMT3A mut/NPM1wt/FLT3-ITDwt）,double-mutation group B and C:（DNMT3Amut/NPM1mut/FLT3-ITDwt,DNMT3Amut/NPM1wt/ FLT3-ITDmut）and triple-mutation group D:（DNMT3Amut/NPM1mut/FLT3-ITD mut）.The differences of gender,age,peripheral blood routine,bone marrow cell morphology,chromosome karyotype,immunotyping,gene mutation,curative effect and overall survival were analyzed retrospectively,and the risk factors affecting the prognosis of AML were evaluated.All the clinical data were analyzed by SPSS 22.0 statistical software,the count data were analyzed by chi square test fisher exact probability method,and the comparison between groups were analyzed by two independent samples t test.The measurement data were analyzed by one-way ANOVA.Kaplan Meier curve was used for univariate survival analysis and the Log-rank test was used to compare the the survival differences between groups.COX proportional risk model was used to analyze the factors that may affect survival（P < 0.05）,and it was considered that P <0.05 was statistically significant.Results:1.According to the gene mutation situation points: the incidence of DNMT3 Awt and DNMT3 Amut were 75.3%（146/194）and 24.7%（48/194）,the hot spot mutation to R882 locus accounted for 19%（R882H n=27,R882 C n= 7,R882 other n= 3）,and the non-R882 was 5.7%.2.Further divided according to DNMT3 mutation accompanied by NPM1/FLT3-ITD mutation : DNMT3Amut/NPM1wt/FLT3ITDwt（group A）Incidence rate 31.3%（15/48）、DNMT3Amut/NPM1mut/FLT3-ITDwt（group B）Incidence rate 27.1%（13/48）、DNMT3Amut/NPM1wt/FLT3-ITDmut（group C）Incidence rate 16.7%（8/48）、 DNMT3Amut/NPM1mut/ FLT3-ITDmut（group D）Incidence rate 25%（12/48）.3.In terms of gender and age,there was no significant difference between DNMT3 Awt and DNMT3 Amut and among the four groups with or without NPM1/FLT3-ITD mutation in DNMT3 A mutation（P > 0.05）.4.In the FAB classification,M4/M5 subtype was the most common in AML patients with DNMT3Amut（29.2%,54.2%）,while there was no significant difference in the distribution of FAB subtypes among the four groups with or without NPM1/FLT3-ITD mutation in DNMT3 A mutation.5.In terms of hematological characteristics,the peripheral blood WBC、HGB、PLT、Blasts in AML patients with DNMT3 Amut were significantly higher than those in DNMT3 Awt.Among the four groups with or without NPM1/FLT3-ITD mutation in DNMT3 A mutation,the WBC count and blasts percentage in group D were higher than those in the control group（group A）（P < 0.05）,but there was no significant difference between group B and group C and the control group（group A）.6.In comparison with DNMT3 Awt,NPM1,FLT3-ITD,IDH1/2 and TET2 genes are frequently associated with DNMT3 mut,and the probability of CEBPA gene mutation is low;Among the four groups DNMT3 mutation with NPM1/FLT3-ITD mutation,group B has statistically higher probability of TET2 gene mutation than the control group（group A）.7.In terms of the number of gene mutations,there were more likely to have 3 or more gene mutations in DNMT3 Amut than DNMT3 Awt patients and group D than the control group（group A）,and the differences were statistically significant（P < 0.05）.8.In terms of immunophenotype,Compared with DNMT3 Awt,DNMT3A mut was related to the deficiency of CD34 and HLA-DR.Further analysis of the immunotyping among the four groups showed that the expression rate of CD34 in groups B and D was statistically lower than that in the control group（P<0.05）.9.In terms of chromosomal karyotype distribution,AML patients with DNMT3 Amut had more normal karyotypes（NK）than DNMT3 Awt,but there was no significant difference between the two groups（P > 0.05）;At the same time,there was no difference in karyotype distribution among the four groups with or without NPM1/FLT3-ITD mutation in DNMT3 A mutation（P > 0.05）.10.In terms of prognostic stratification,there was a significant difference between DNMT3 Awt and DNMT3Amut（P = 0.007）.The mutant type was more likely to be distributed in the group with moderate prognosis and poor prognosis,and the moderate prognosis was the most common.Among the four groups with or without NPM1/FLT3-ITD mutation in DNMT3 A mutation,it was found that the proportion of good prognosis in group B and the proportion of poor prognosis in group C was statistically higher than that in the control group（group A）（P = 0.059）.11.Comparison of the efficacy of first induction chemotherapy,DNMT3 Amut has statistically higher NR and lower CR than that of DNMT3Awt（P < 0.001）;After comparing the first induced remission among the four groups,it was found that the first CR rate in group B was the highest,but the difference was not statistically significant（P > 0.05）.12.In the comparison of long-term effect,the OS rate and median OS of DNMT3 Amut patients were significantly lower than those of DNMT3Awt（P < 0.001）;After comparing the long-term effects of the four groups,it was found that the OS rate and med ian OS of group B was statistically longer than that of the control group（group A）.While there was no significant difference between group C and group D and the control group.13.Multivariate regression analysis of COX model indicated that DNMT3 A gene（P=0.003）,first induction remission（P=<0.001）and NCCN prognostic risk stratification（P=0.003）were independent prognostic factors for OS in AML patients.Conclusions:1.In AML patients,the DMNT3 A mutation rate was 24.7%,and the hot spot mutation was R882,mainly R882H（13.9%）.DMNT3 Amut mainly occurs in M4/M5 subtype and moderate prognosis and normal karyotype,often accompanied by NPM1 and FLT3-ITD gene mutations,less CEBPA mutations,and is associated with CD34 and HLA-DR deficiency.2.Compared with DMNT3 Awt,AML patients with DNMT3 Amut had the characteristics of high peripheral blood WBC、HGB、PLT and high Blast,lower OS rate and first CR rate,and shorter median OS.3.When DNMT3Amut/NPM1 mut,NPM1mut can attenuate the adverse prognostic effect of DNMT3 Amut on AML patients.DNMT3 Amut /FLT3-ITDmut/NPM1 mut is an independent prognostic subtype.When these three gene mutations coexist,the OS rate and CR rate are lower,indicating that the beneficial effect of NPM1 on prognosis is offset.4.NCCN prognostic stratification,first induced remission and DMNT3 A gene mutation were independent prognostic factors for OS in patients with AML. |
PDF Full Text Request