We used the flow cytometric immunoassay to study the correlation between the tumor-suppressor gene product p53- and the DNA ploidy in 30 de novo cases of acute nonlymphocytic leukemia (ANLL).The results showed that 15...We used the flow cytometric immunoassay to study the correlation between the tumor-suppressor gene product p53- and the DNA ploidy in 30 de novo cases of acute nonlymphocytic leukemia (ANLL).The results showed that 15 cases were negative and the other 15 cases were positive expression for p53. As compared with p53 negative (p53) cases, the patients with positive p53 (p53+) had higher percentage of bone marrow blasts and lower peripheral leukocyte and platelet counts,which had no influence on the complete remission rate. Before treatment, DNA diploidy was seen in 18 cases including 12 p53- cases, and DNA aneuploidy in 12 cases including 9 p53+. After therapy, aneuploidy could be transformed into diploidy.Patients with P53+ or having aneuploidy in complete remission were at risk for early relapse. We believe that p53 may be involved in the process of leukemogenesis and progression of ANLL.展开更多
Runt-related transcription factor 1(RUNX1)is an essential regulator of normal hematopoiesis.Its dysfunction,caused by either fusions or mutations,is frequently reported in acute myeloid leukemia(AML).However,RUNX1 mut...Runt-related transcription factor 1(RUNX1)is an essential regulator of normal hematopoiesis.Its dysfunction,caused by either fusions or mutations,is frequently reported in acute myeloid leukemia(AML).However,RUNX1 mutations have been largely under-explored compared with RUNX1 fusions mainly due to their elusive genetic characteristics.Here,based on 1741 patients with AML,we report a unique expression pattern associated with RUNX1 mutations in AML.This expression pattern was coordinated by target repression and promoter hypermethylation.We first reanalyzed a joint AML cohort that consisted of three public cohorts and found that RUNX1 mutations were mainly distributed in the Runt domain and almost mutually exclusive with NPM1 mutations.Then,based on RNA-seq data from The Cancer Genome Atlas AML cohort,we developed a 300-gene signature that significantly distinguished the patients with RUNX1 mutations from those with other AML subtypes.Furthermore,we explored the mechanisms underlying this signature from the transcriptional and epigenetic levels.Using chromatin immunoprecipitation sequencing data,we found that RUNX1 target genes tended to be repressed in patients with RUNX1 mutations.Through the integration of DNA methylation array data,we illustrated that hypermethylation on the promoter regions of RUNX1-regulated genes also contributed to dysregulation in RUNX1-mutated AML.This study revealed the distinct gene expression pattern of RUNX1 mutations and the underlying mechanisms in AML development.展开更多
尽管治疗的进步极大地改善了急性白血病患者的预后和生存,但时至今日多数类型的急性白血病没有特异性的生物标记,因此对于多数白血病患者,影响生存的复发这一重要因素缺少有效的预警机制。ID4基因启动子区甲基化广泛发生于各类型急性白...尽管治疗的进步极大地改善了急性白血病患者的预后和生存,但时至今日多数类型的急性白血病没有特异性的生物标记,因此对于多数白血病患者,影响生存的复发这一重要因素缺少有效的预警机制。ID4基因启动子区甲基化广泛发生于各类型急性白血病。本研究在前期建立的甲基化定量PCR体系的基础上,用该方法检测患者骨髓样本,探讨ID4甲基化定量指标(percentage of methylated reference,PMR)的临床意义。采集我院门诊及住院确诊的初治、完全缓解、复发3个阶段的急性白血病患者骨髓样本及正常对照者骨髓样本。应用ID4甲基化定量PCR体系对样本进行检测。按初治、完全缓解、复发分组比较PMR值。比较相同病例不同疾病状态的PMR的动态变化。结果表明,初治组PMR最高,其次为复发组,而完全缓解组最低。初治组PMR与完全缓解组比较存在统计学差异。4例随访病例的PMR值波动与病情变化一致。在1例复发病例中,PMR升高早于骨髓细胞学检查确认复发1.7个月。结论:本研究通过ID4基因启动子区甲基定量检测的方法初步验证:甲基化水平的量化指标PMR值与急性白血病患者肿瘤细胞负荷关系密切。PMR动态监测波动与疾病变化一致,可能具有预测复发的作用,但ID4甲基化定量指标的临床价值还有待进一步研究证据的支持。展开更多
文摘We used the flow cytometric immunoassay to study the correlation between the tumor-suppressor gene product p53- and the DNA ploidy in 30 de novo cases of acute nonlymphocytic leukemia (ANLL).The results showed that 15 cases were negative and the other 15 cases were positive expression for p53. As compared with p53 negative (p53) cases, the patients with positive p53 (p53+) had higher percentage of bone marrow blasts and lower peripheral leukocyte and platelet counts,which had no influence on the complete remission rate. Before treatment, DNA diploidy was seen in 18 cases including 12 p53- cases, and DNA aneuploidy in 12 cases including 9 p53+. After therapy, aneuploidy could be transformed into diploidy.Patients with P53+ or having aneuploidy in complete remission were at risk for early relapse. We believe that p53 may be involved in the process of leukemogenesis and progression of ANLL.
基金supported in part by the National Natural Science Foundation of China(Nos.81890994,81770153,81530003,and 81911530240)the National Key Research and Development Program of China(No.2019YFA0905900).
文摘Runt-related transcription factor 1(RUNX1)is an essential regulator of normal hematopoiesis.Its dysfunction,caused by either fusions or mutations,is frequently reported in acute myeloid leukemia(AML).However,RUNX1 mutations have been largely under-explored compared with RUNX1 fusions mainly due to their elusive genetic characteristics.Here,based on 1741 patients with AML,we report a unique expression pattern associated with RUNX1 mutations in AML.This expression pattern was coordinated by target repression and promoter hypermethylation.We first reanalyzed a joint AML cohort that consisted of three public cohorts and found that RUNX1 mutations were mainly distributed in the Runt domain and almost mutually exclusive with NPM1 mutations.Then,based on RNA-seq data from The Cancer Genome Atlas AML cohort,we developed a 300-gene signature that significantly distinguished the patients with RUNX1 mutations from those with other AML subtypes.Furthermore,we explored the mechanisms underlying this signature from the transcriptional and epigenetic levels.Using chromatin immunoprecipitation sequencing data,we found that RUNX1 target genes tended to be repressed in patients with RUNX1 mutations.Through the integration of DNA methylation array data,we illustrated that hypermethylation on the promoter regions of RUNX1-regulated genes also contributed to dysregulation in RUNX1-mutated AML.This study revealed the distinct gene expression pattern of RUNX1 mutations and the underlying mechanisms in AML development.
文摘尽管治疗的进步极大地改善了急性白血病患者的预后和生存,但时至今日多数类型的急性白血病没有特异性的生物标记,因此对于多数白血病患者,影响生存的复发这一重要因素缺少有效的预警机制。ID4基因启动子区甲基化广泛发生于各类型急性白血病。本研究在前期建立的甲基化定量PCR体系的基础上,用该方法检测患者骨髓样本,探讨ID4甲基化定量指标(percentage of methylated reference,PMR)的临床意义。采集我院门诊及住院确诊的初治、完全缓解、复发3个阶段的急性白血病患者骨髓样本及正常对照者骨髓样本。应用ID4甲基化定量PCR体系对样本进行检测。按初治、完全缓解、复发分组比较PMR值。比较相同病例不同疾病状态的PMR的动态变化。结果表明,初治组PMR最高,其次为复发组,而完全缓解组最低。初治组PMR与完全缓解组比较存在统计学差异。4例随访病例的PMR值波动与病情变化一致。在1例复发病例中,PMR升高早于骨髓细胞学检查确认复发1.7个月。结论:本研究通过ID4基因启动子区甲基定量检测的方法初步验证:甲基化水平的量化指标PMR值与急性白血病患者肿瘤细胞负荷关系密切。PMR动态监测波动与疾病变化一致,可能具有预测复发的作用,但ID4甲基化定量指标的临床价值还有待进一步研究证据的支持。
