Study On The Characteristics Of Aging And EZH2 Mutation And Expression In Adult Acute Lymphoblastic Leukemia

Part Ⅰ Characteristics and Clinical Outcomes of Acute Lymphoblastic Leukemia in Elderly PatientsObjective This study is aim at exploring the differences in clinical and laboratory parameters between elderly and non-elderly patients with acute lymphoblastic leukemia(ALL).Poor prognostic factors in elderly patients were explored to guide the individualized treatment.Methods Two hundred and seventy-nine ALL patients were divided into two groups,elderly group with their age more than 60 years(60-79y)and non-elderly group with their age less than 60 years(14-59y).The differences in clinical and laboratory parameters;abnormal molecular genetics on related genes,including IKZF1,PAX5,NOTCH1,PHF6,SH2B3,LEF1,and JAKI as well as the correlations with treatment response and clinical outcome were compared between the two groups.Results Males accounted for a smaller part in the elderly group(42.9%61.7%,P=0.015).The percentage of B cell ALL(B-ALL),Philadelphia chromosome positive(Ph+)and CD3 3 positive rate were higher in the elderly compared with those in the non-elderly patients(87.8%vs.70.4%,P=0.009;47.8%vs.27.4%,P=0.007;56.8%vs.39.0%,P=0.049,respectively).While both lymphodenopathy and total complete remission(CR)rate gained the upper hand in non-elderly group(38.9%vs.20.0%,P=0.016;91.3%vs.68.3%,P<0.001,respectively).Moreover,the elderly had lower 3-month,6-month,12-month and 24-month overall survival(OS)rate(64.6%vs.84.4%,P=0.001;50.0%vs.73.8%,P=0.001;29.2%vs.52.4%,P=0.003;6.2%26.2%,P=0.003,respectively)compared with non-elderly patients.No significant differences in mutation rates ofPAX5,NOTCHI,PHF6,SH2B3,LEF1 and JAK1 were foundConclusions Compared with non-elderly ALL patients,elderly ones harbor their intrinsic characteristics which might give rise to aninferior outcome.As a consequence,more attention should be poured into treating this particular group of ALL patients to improve the survival in elderly patients with ALL.Part Ⅰ Mutations and overexpression of EZH2 in adult acute Lymphoblastic LeukemiaObjective Enhancer of Zeste homlog 2(EZH2),a histone methyl transferase gene,is an inevitable subunit of epigenetic regulator Polycomb repressive complex 2(PRC2),playing a crucial role in the thimethylation of lysine 27 of histone H3(H3K27me3).Mutations of EZH2 are commomly seen in hematopoietic malignancies,including germinal center lymphomas,myeloid diseases as well as acute acute lymphoblastic leukemia(ALL).Meanwhile,EZH2 often over-expressed in solid tumors and hematopoietic diseases and to some extent addressed the prognostic significance.To elucidate the roles EZH2 mutation and expression played in Chinese adult patients with ALL,this study is therefore conducted.Methods Samples of one hundred and forty-six patients with ALL were screened for EZH2 mutations(exons 2,8,10,11,15,16,18,19,and 20).The co-existing of EZH2,NOTCH1,PHF6 and IL7R mutations were explored.One-hundred and twenty-six adult ALL patients and 37 normal people were included to detect EZH2 expression through real-time quantitative polymerase chain reaction(PCR).Statistical analysis was carried out using the SPSS(Version 20.0)and Graph Pad 5.0.EZH2 mutation statuswas analysed.White blood cell(WBC),blasts in the sample of bone marrow(BM)or peripheral blood(PB),extramedullary infiltration incidence and other parameters were compared between EZH2 high and low expression group.Quantitative data were analysed with nonparametric Mann-Whitney test and qualitative datawith Pearson’s chi-square test or Fisher’s exact test.Kaplan-Meier curves were used to assess survival.P values below 0.05 were considered statistically significant.ResultsFinally,3 EZH2 mutations(D730fs*,K466T and T467fs*)in 2 adult ALL patients of 146 individuals(2/146)were discovered and both of whom respond poorly to the treatment.The patient with EZH2 D730fs*1(Mu#1)was diagnosed as early T cell precursor ALL(ETP-ALL)and relapsed for 5 five times before he died.Moreover,a notable finding was that EZH2 mutation co-existed with NOTCH1.IL7R,and PHF6 mutations in the EZH2 mutated patients.Also,we found that EZH2 was overexpressed in 50%adult ALL patients and the EZH2 high expression was associated with high risk leukemia factors(high WBC and blasts),higher extramedullary infiltration rate,and inferior responses parameters to treatment,including lower complete remission(CR)rate as well as relapse and refractory rate.ConclusionsTaken together,data available indicated that EZH2 mutations,as well as its overexpression gave rise to a complicated and tough clinical process,predicting an unsatisfied response to chemotherapy and might,more or less,affected the prognosis of adult ALL patients,though,no prognostic significance was seen in individuals with high or low EZH2 expression statisticallnjy for the present.