Chinese and Europeans with Acute Myeloid Leukemia Have Different Topologies of Mutations
Bin YinXiaofeng HanHongyu HuangJiawei YinMin ZhangHuikai MiaoFan ZhangHong LiuHongchao YinJiang HuXuejun HongYan ZengDepei WuRobert Peter Gale
0
Citation
0
Reference
20
Related Paper
Keywords:
CEBPA
NPM1
IDH2
To investigate the incidence, molecular features and clinical significance of CCAAT/enhancer binding protein alpha (CEBPA) gene mutation in patients with acute myeloid leukemia (AML).Mutation analysis of the entire coding region of CEBPA gene in 206 de novo AML patients was performed by using polymerase chain reaction (PCR) followed by sequence analysis and fragment length analysis.Of 206 AML patients, 31 (15%) had CEBPA gene mutations, including 23 with double mutations (duCEBPA) and 8 with single mutation (siCEBPA). CEBPA gene mutations presented mainly in M2 subtype or intermediate risk patients. As compared with those with wild type CEBPA gene, patients with mutated CEBPA gene were of higher white blood cell counts [20.92(0.86-351.43)× 10(9)//L vs 8.17(0.47-295.2) × 10(9)/L, P=0.003], higher hemoglobin levels [97.5(51-128) g/L vs 80.5(13-153) g/L, P=0.015] and lower platelet counts [27.5(5-81)× 10(9)//L vs 44(3-548)× 10(9)/L, P=0.004]. Patients with CEBPA gene mutation had higher complete remission (CR) rate than those with wild type (P=0.009). While co-existing of NPM1 and siCEBPA mutations was observed in M5 subtype (2/8, 25%), NPM1 gene mutation was not present in any patients with duCEBPA mutation (0/23, 0%). Dynamic tracking analysis showed that CEBPA mutations disappeared at CR, and the same mutations re-appeared at relapse. When compared to sequence analysis, the coincidence rate of CEBPA mutations detected by fragment length analysis was 100% (54/54).CEBPA gene mutation is a recurring genetic change in AML patients and has a certain correlation with clinical and laboratory features. It could be reliably used as a potential marker for minimal residual disease follow up. The prognostic significance of co-existing of siCEBPA with NPM1 mutations in patients with AML-M5 subtype needs further investigation.
CEBPA
NPM1
Cite
Citations (4)
NPM1
CEBPA
Nonsense mutation
Cite
Citations (13)
To explore the coexisting mutations in IDH-mutated acute myeloid leukemia(AML) and its relation with partial clinical parametrs.The exon 4 mutation of IDH1/2 gene was screened by using genome DNA-PCR combined with sanger sequencing, 51 targeted gene mutations in the patients with IDH1/2 mutation were detected by using high throughput DNA sequencing combined with sanger sequencing.Among 358 patients, the IDH1/2 mutation was found in 46 cases including IDH1 mutation in 35 cases and IDH2 mutation in 11 cases, 97.87%(45/46) patients with IDH1/2 mutation simultaneously carried other gene mutations including 8(17.8%) cases with mutation of double gene, 17(37.8%) cases with mutation of 3 genes and 20(44.4%) cases with mutation of ≥ 4 genes. The mutation frequency of each patient averaged 3.52 times. In mutation of accompanied genes, the common genes were NPM1(n=29, 63.0%), next DNMT3A(n=25, 54.3%), FLT3-ITD(n=7, 15.2%), TET2(n=5, 10.9%) and NRAS(n=5, 10.9%). The average WBC level of patients with NPM1 mutation in IDH1 mutation group was higher than that of patients in wild type group(P<0.05). The complete remission (CR) rate of patients with DNMT3A mutation was significant lower than that of patients with wild type (30% vs 80%, P<0.01). The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than that in the patients with double mutations(P<0.05).More than 95% AML patients with IDH1/2 mutation commonly show additional mutations. The number and the type of IDH coexisting mutations have certain effect on the clinical features and CR rate.急性髓系白血病中与IDH1/2突变共存的基因突变分析.探讨急性髓系白血病（AML）患者中与IDH1/2突变共存的基因突变及其与部分临床参数的相关性。.采用基因组DNA-PCR联合Sanger测序法筛选IDH1/2基因4号外显子突变；采用高通量DNA测序联合Sanger测序法检测IDH1/2突变患者51种肿瘤靶基因突变.358例患者中共检出46例IDH1/2突变，其中35例IDH1突变，11例IDH2突变。97.8%（45/46）IDH1/2突变患者同时携带其他基因突变，其中双基因突变8例，3个基因突变共存17例，≥4个基因突变共存20例。每例患者平均突变3.52次。伴随基因突变中最常见的基因为NPM1（n=29，63.0%），其他依次为： DNMT3A（n=25，54.3%）、FLT3-ITD(n=7，15.2%)、TET2（n=5，10.9%）及NRAS（n=5，10.9%）。在IDH1突变组中，伴NPM1突变者的平均外周血白细胞水平高于正常者，伴DNMT3A突变患者的CR率明显低于正常者，差异均有统计学意义（P=0.034，0.003）；≥4个基因突变患者的白细胞水平明显高于双基因突变者，差异显著（P=0.037）.95%以上伴IDH1/2突变的AML患者同时存在额外基因突变，基因突变个数及突变类型对患者的临床特征及CR率有一定的影响.
Sanger sequencing
NPM1
IDH2
Cite
Citations (1)
To assess the prognostic role of myeloid transcription factor gene CEBPA (CCAAT/enhancer binding protein-α), a novel gene involved in leukemia in Egyptian adults AML.Screening for CEBPA mutations was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP) in pretreatment bone marrow samples from 55 newly diagnosed adult AML.CEBPA mutations were found in 11 (20%) of 55 AML patients. They had significantly higher hemoglobin (P = 0.037), and lower LDH (P = 0.003) levels when compared to those without. CEBPA mutations were frequently detected in M4 (45.5%) and M2 (27.2%) subtypes, and significantly associated with normal karyotype (90.9%, P = 0.007). We distinguished six cases with two different mutations or one homozygous mutation (CEBPA(double-mut)) as well as five cases with only one single heterozygous mutation (CEBPA(single-mut)). Patients with CEBPA mutations had significantly higher complete remission (P = 0.047), lower mortality (p = 0.047). Double CEBPA mutant cases showed longer disease free survival (DFS) and overall survival (OS) when compared to wild type CEBPA (for DFS; median = 27 versus 24 months respectively; P = 0.009 and for OS; median = 28 versus 25 months respectively; p = 0.008). No significant differences were found between CEBPA(single-mut) cases and wild type cases regarding DFS and OS (for DFS; median = 13 versus 24 months respectively; P = 0.615 and for OS; median = 14 versus 25 months respectively; P = 0.703).CEBPA mutation status is known to be a prognostic factor for favorable outcome in AML patients. CEBPA(double-mut) is associated with favorable DFS and OS. In contrast, CEBPA(single-mut) AMLs survival studies did not differ significantly with wild-type cases. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Based on these findings, we propose that CEBPA(double-mut) should be clearly defined from CEBPA(single-mut) AML and considered as a separate entity in the classification of AML. Furthermore, incorporation of CEBPA mutation status into novel risk-adapted therapeutic strategies in Egypt will improve the currently disappointing cure rate of this group of patients.
CEBPA
Cite
Citations (9)
To characterize the mutational profile of patients with core-binding factor acute myeloid leukemia (CBF-AML).A total of 81 acute myeloid leukemia patients were recruited, which included 36 cases of CBF-AML and 45 cases of cytogenetically normal acute myeloid leukemia (CN-AML) . Mutations of FLT3-ITD, FLT3-TKD, NPM1, c-KIT, NRAS, KRAS, TET2, IDH1/2, RUNX1, DNMT3A, GATA2, ASjXL1, TP53, PTPN11, JAK2V617F, SETBP1 and CEBPA genes were simultaneously detected by DNA-based PCR and Sanger sequencing.Over all, mutations were detected in 68 patients (83.9%), with the most common ones including double CEBPA mutations (n=17), followed by NPM1 (n=15), c-KIT (n=11), NRAS (n=10), TET2 (n=9), FLT3-TKD (n=9), FLT3-ITD (n=8), IDH1 (n=7), RUNX1 (n=7), KRAS (n=7), DNMT3A (n=6), IDH2 (n=4), and GATA2 (n=4) mutations. AML1-ETO and CBFβ-MYH11 fusions were present in 21 and 15 patients, respectively. Coexistence of ≥2 mutations was more common in CN-AML comparing with CBF-AML. The mutation rate of NPM1, FLT3-ITD, DNMT3A, IDH1 and CEBPA double mutations were higher in patients with CN-AML. NRAS, c-KIT and KRAS mutations were identified more frequently in patients with CBF-AML (P<0.05). Based on the function, aberration of genes involved in DNA methylation, NPM1 proteins and transcription predominated in CN-AML, while tyrosine kinase receptor signaling and RAS pathways have predominated in CBF-AML.The genomic landscape of CBF-AML patients has differed from that of CN-AML patients. Synergy of fusion genes with particular mutations may impact the clinical phenotype and prognosis of patients.
CEBPA
NPM1
Core binding factor
RUNX1T1
Cite
Citations (0)
NPM1
Cite
Citations (1)
To determine whether the distinct and heterogeneous WHO category called "AML with myelodysplasia-related changes" (MRC-AML), presents specific molecular alterations we searched for mutations in genes known to be mutated in malignant myeloid diseases. In 48 MRC-AML patients analyzed, we found 17 mutations in ASXL1 (35%), eight in RUNX1 (17%), seven in TET2 (15%), 12 in IDH (n = 2) or IDH2 (n = 10) (25%), four in DNMT3A (8%), four in NPM1 (8%), and one in FLT3 (2%). Mutations were more frequent in the intermediate cytogenetic (IC) subgroup of 36 patients than in the unfavorable karyotype subgroup, with an average ratio mutations/patients of 1.36 [0-3] vs. 0.33 [0-2] (P < 0.001). Then, we compared these 36 patients with IC MRC-AML with a control panel of 37 no-MRC-AML patients, who had both IC and no dysplasia. IC MRC-AMLs were associated with higher incidence of ASXL1 mutations (47% vs. 0%, P < 0.001) and lower incidence of DNMT3A (6% vs. 38%, P = 0.001), NPM1 (11% vs. 62%, P < 0.001) and FLT3 (3% vs. 49%, P < 0.001) mutations. No difference was found in the incidence of IDH1/2 or TET2 mutations according to the presence of dysplasia. Complete remission rate after intensive treatment was lower in the MRC-AML group than in the no-MRC-AML group (48% vs. 78%, P = 0.023) and in wild type NPM1 patients (50% vs. 84%, P = 0.009). Our study showed that MRC-AML as defined in the WHO 2008 classification presents a specific mutation pattern characterized by a high frequency of ASXL1 mutations and a low rate of NPM1, FLT3, and DNMT3A mutations.
NPM1
CEBPA
RUNX1
Cite
Citations (68)
NPM1
IDH2
CEBPA
Sanger sequencing
Cite
Citations (0)
This study was purposed to detect the mutation of isocitrate dehydrogenase 1 (IDH-1) gene in patients with acute myeloid leukemia (AML) and to explore its clinical significance. The genomic DNA was extracted from mononuclear cells (MNC) of bone marrow or peripheral blood in 205 adult AML patients, the exon 4 of IDH1 gene was amplified by PCR, then the sequencing and comparison were performed. The results showed that IDH1 mutation was detected in 9 (4.39%) of 205 AML patients. There were 6 cases of R132H mutation, 1 of R132L mutation, 1 of R132G mutation and 1 of R132S mutation. Significantly more IDH1 aberrations were detected in AML-M2 (P = 0.002) than other types. And the 9 patients with IDH1 mutation were characterized by low platelet count which was lower than patients with wild type IDH1 (P = 0.003). IDH1 mutation combined with FLT3/ITD mutation was found in 5 cases, c-kit mutation in 1, NPM1 mutation in 2, and IDH1 mutation with CEBPA or WT1 mutation was not found, which revealed a significant interaction between IDH1 mutation and the FLT3/ITD positive genotype or the CEBPA wild-type. IDH1 mutation were detected in 4 of 71 (5.63%) CN-AML. There was no significant difference of IDH1 mutation incidence between the normal and abnormal karyotypes. It is concluded that the rate of IDH1 mutation was 4.39% in Chinese AML patients. IDH1 mutation is significantly associated with AML-M2, lower platelet counts in peripheral blood, FLT3/ITD mutation and CEBPA wild-type, but not with age, white blood cell count in peripheral blood, karyotype, NPM1, c-kit or WT1 mutation.
CEBPA
Isocitrate dehydrogenase
NPM1
Cite
Citations (1)