Cytogenetics And Epigenetics Of Acute Leukemia

Acute leukemia(AL) is a group of heterogeneous diseases in terms of morphology, cytogenetics,immunophenotypes,molecular genetics and clinical characteristics.In the last decades,with the development of cytogenetics and molecular genetics, karyotyping has become one of the routine tests in the clinical practice,and plays an important role in the diagnosis and prognosis of AL.However,the majority of data reported were based on the calculation of the western countries.Recently,ettmic disparities of hematological malignancies were reported.Nevertheless,most of those studies were limited to small numbers of cases.Few large-scale studies are available in the medicine literature,especially for the Chinese population.It was on this background that we started a retrospective study on cytogenetics of more than 2 000 AL patients who received cytogenetic analyses in our institution during the previous decade.We calculated the population incidence of specific chromosome abnormalities and compared the main results with reports from other countries,so as to deliver a global picture of the cytogenetics of the Chinese AL patients.On the other hand,as the most important part of the emerging epigenetics and epigenomics,methylation of CpG island resulting in the inhibited expression of cancer suppressor genes,as well as its impact on the pathogenesis and progression of tumors has become a hot issue.Animal models with AL-specific chromosomal translocations/inversions failed to develop overt leukemia,suggesting that sole genetic change is not enough for the development of hematological malignancies.In most cases,epigenetic modifications might be involved.Though aberrant hypermethylation of tumor suppressor genes is now known as a common phenomenon in the leukemic blasts,the relationship between methylation and prognosis was reported only for several genes.Here we studied the methylation status of five genes in AL samples and analysed the correlation between methylation and patients' clinical features and prognosis.PartⅠCytogenetics of acute myeloid leukemia:a study based on 1432 patientsObjectives:To study the cytogenetic characteristic of acute myeloid leukemia(AML), the incidences of major chromosome aberrations and the disparity between different races.Methods:We performed a retrospective study on the cytogenetic findings of 1 432 de novo AML patients who received cytogenetic analyses in our institution between 1994 and 2007,and compared the main results with representational large-scale studies from other countries.Results:Of the 1 432 patients,1 293 patients received successful cytogenetic analyses (90%).Clonal abnormalities were detected in 746 cases(58%).The abnormal rate was comparable to previous reports.The most frequent chromosome abnormality was t(15;17),detected in 14%of the successful cases,followed by t(8;21),in 8%,and t(9;22),+21 and +8,each in 2%.For different FAB subtypes,translocation was most common in M3 patients,detected in 58%;deletion was most common in M1,detected in 18%;and trisomy was most common in M5,detected in 29%.Complex karyotypes were most frequent in M0 patients,detected in 17%.The total incidence of AML increased with age between 0 and 60 years,that was from 0.3 case/100 000 inhabitants at 0-9 years to 6.2 cases/100 000 inhabitants at 50-59 years;and decreased with age above 60 years,that was from 4.9 cases/100 000 inhabitants at 60-69 years to 1.4 cases/100 000 inhabitants above 80 years.Conclusion:More than a half of the de novo AML patients harbored clonal chromosome abenations.The distribution of FAB subtypes,age of diagnosis and the incidences of major karyotypic abnormalities showed ethnic disparity.PartⅡCytogenetics of acute lymphoid leukemia:a study based on 585 patientsObjectives:To study the cytogenetic characteristic of acute lymphoid leukemia(ALL), the incidences of major chromosome aberrations and the disparity between different races.Methods:We performed a retrospective study on the cytogenetic findings of 585 de novo ALL patients who received cytogenetic analyses in our institution between 1994 and 2007,and compared the main results with representational large-scale studies from other countries.Results:Of 585 ALL patients,551 patients received successful cytogenetic analyses (94%).Clonal chromosome aberrations were detected in 300 cases(49%).High hyperdiploid(defined as more than 50 chromosomes) was observed in 119 cases(22%). The most frequent chromosomal translocation was t(9;22),detected in 11%cases, followed by 11q23 rearrangements and abnormalities of T-cell receptor(TCR),each in 2%.Complex karyotypes without established translocations were detected in 20 cases (4%).We calculated the age-specific incidences of ALL based on the population of Zhejiang Province.There appeared to be two age peaks for ALL.The first was at 15-19 years,with an incidence of 2.4 cases/100 000 inhabitants.The second was at 55-59 years,with an incidence of 2.3 cases/100 000 inhabitants.Conclusion:Nearly a half of the de novo ALL patients had clonal chromosome aberrations.The age distribution and the incidences of main chromosome abnormalities showed ethnic disparity.PartⅢPredictive value of DNA methylation in patients with acute myeloid leukemiaObjectives:To study the methylation status of DKK3,TMS1,DAPK,ASPP1 and WIF1 in acute myeloid leukemia(AML) and the potential predictive value of' DNA methylation in AML.Methods:The methylation status of DKK3,TMS1,DAPK,ASPP1 and WIF1 in pretreatment bone marrow samples from 71 patients with de novo AML was measured by methylation-specific polymerase chain reaction(MSP).The correlation between methylation and clinical features as well as prognosis of AML patients was analysed.Results:In 71 samples,the methylation frequency of DKK3 was 63.4%(45/71),and the methylation frequency of DAPK was 60.6%(43/71).The methylation of TMS1, ASPP1 and WIF1 was not detected in any of our samples.Chisquare test showed a significant correlation between the methylation status of DKK3 and DAPK(P=0.006). The methylation frequency of DAPK was significantly higher in patients above 60 years(87.5%vs.57.1%,P=0.037).The mean peripheral WBC count of patients with DAPK methylation was significantly higher than those without(57.2×109/L vs. 11.2×109/L,P=0.017).Besides,the complete remissionrate after one course of induction for patients without DAPK methylation was 92.3%,significantly higher than that for patients with DAPK methylation(54.2%).Kaplan-Meier sruvival curve for patients with intermediate-risk karyotypes who received adequate chemotherapy indicated that the mean Recurrence-free Survival(RFS) of patients with DAPK methylation was significantly shorter than that of patients without DAPK methylation (13.2 months vs.24.8 months,P=0.045).Conclusion:Promoter hypermethylation of tumor suppressor genes was common in de novo AML patients.DNA methylation was one of the most important factors to chemotherapy effects and RFS.