Refinement of the prognostic impact of somatic CEBPA bZIP domain mutations in acute myeloid leukemia: Results of the AML Study Group (AMLSG).
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ABSTRACT:
SUBMITTER: Rucker FG
PROVIDER: S-EPMC11247273 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Refinement of the prognostic impact of somatic <i>CEBPA</i> bZIP domain mutations in acute myeloid leukemia: Results of the AML Study Group (AMLSG).
Rücker Frank G FG Corbacioglu Andrea A Krzykalla Julia J Cocciardi Sibylle S Lengerke Claudia C Germing Ulrich U Wulf Gerald G Samra Maisun A MA Teichmann Lino L LL Lübbert Michael M Kühn Michael W M MWM Bentz Martin M Westermann Jörg J Bullinger Lars L Gaidzik Verena I VI Meid Annika A Aicher Sophia S Stegelmann Frank F Weber Daniela D Schrade Anika A Thol Felicitas F Heuser Michael M Ganser Arnold A Benner Axel A Döhner Hartmut H Döhner Konstanze K
HemaSphere 20240715 7
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Project description:Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.
| S-EPMC8753195 | biostudies-literature
Project description: Not available
| S-EPMC11004125 | biostudies-literature
Project description:CEBPA mutations have been associated with improved outcome in adult acute myeloid leukemia (AML). We evaluated the prevalence and prognostic significance of CEBPA mutations in 847 children with AML treated on 3 consecutive pediatric trials. Two types of CEBPA mutations-N-terminal truncating mutations and in-frame bZip-domain mutations-were detected in 38 (4.5%) of 847 patients tested; 31 (82%) of 38 patients with mutations harbored both mutation types. Mutation status was correlated with laboratory and clinical characteristics and clinical outcome. CEBPA mutations were significantly more common in older patients, patients with FAB M1 or M2, and patients with normal karyotype. Mutations did not occur in patients with either favorable or unfavorable cytogenetics. Actuarial event-free survival at 5 years was 70% versus 38% (P = .015) with a cumulative incidence of relapse from complete remission of 13% versus 44% (P = .007) for those with and without CEBPA mutations. The presence of CEBPA mutations was an independent prognostic factor for improved outcome (HR = 0.24, P = .047). As CEBPA mutations are associated with lower relapse rate and improved survival, CEBPA mutation analysis needs to be incorporated into initial screening for risk identification and therapy allocation at diagnosis.
| S-EPMC2943755 | biostudies-literature
Project description:Biallelic CEBPA mutations are associated with favorable outcomes in acute myeloid leukemia (AML). We evaluated the clinical and biologic implications of CEBPA-basic leucine zipper (CEBPA-bZip) mutations in children and young adults with newly diagnosed AML. CEBPA-bZip mutation status was determined in 2958 patients with AML enrolled on Children's Oncology Group trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next-generation sequencing (NGS) was performed in 1863 patients (107 with CEBPA mutations) to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160 (5.4%) of 2958 patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPA-dm]) and 28 (17.5%) had a single CEBPA-bZip only mutation. The clinical and laboratory features of the 2 CEBPA cohorts were very similar. Patients with CEBPA-dm and CEBPA-bZip experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (P = .259); this compared favorably to EFS of 46% and OS of 61% in patients with CEBPA-wild-type (CEBPA-WT) (both P < .001). Transcriptome analysis demonstrated similar expression profiles for patients with CEBPA-bZip and CEBPA-dm. Comprehensive NGS of patients with CEBPA mutations identified co-occurring CSF3R mutations in 13.1% of patients and GATA2 mutations in 21.5% of patients. Patients with dual CEBPA and CSF3R mutations had an EFS of 17% vs 63% for patients with CEBPA-mutant or CSF3R-WT (P < .001) with a corresponding relapse rate (RR) of 83% vs 22%, respectively (P < .001); GATA2 co-occurrence did not have an impact on outcome. CEBPA-bZip domain mutations are associated with favorable clinical outcomes, regardless of monoallelic or biallelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR that nullifies the favorable prognostic impact of CEBPA mutations.
| S-EPMC8570058 | biostudies-literature
Project description:Patients with double-mutated CEBPA (CEBPAdm) AML were stratified into favorable risk group, however, few studies have investigated the heterogeneity of different CEBPAdm types in detail. In this study, we analyzed 2211 newly diagnosed AML and identified CEBPAdm in 10.8% of the patients. Within the CEBPAdm cohort, 225 of 239 patients (94.14%) presented with bZIP region mutations (CEBPAdmbZIP) while 14 of 239 patients (5.86%) without bZIP region mutation (CEBPAdmnonbZIP). Analysis of the accompanied molecular mutations showed statistically different incidences of GATA2 mutations between the CEBPAdmbZIP group and the CEBPAdmnonbZIP group (30.29% vs 0%). In the analysis of outcomes, patients with CEBPAdmnonbZIP were associated with shorter overall survival (OS) censored at hematopoietic stem cell transplantation (HSCT) during CR1 compared to those with CEBPAdmbZIP (hazard ratio (HR) = 3.132, 95% confidence interval (CI) = 1.229-7.979, P = .017). Refractory or relapsed AML (R/RAML) patients with CEBPAdmnonbZIP were associated with shorter OS compared to those with CEBPAdmbZIP (HR = 2.881, 95% CI = 1.021-8.131, P = .046). Taken together, AML with CEBPAdmbZIP and CEBPAdmnonbZIP showed different outcomes and might be regarded as distinctive AML entities.
| S-EPMC10205380 | biostudies-literature
Project description:Acute myeloid leukemia (AML) with CEBPA bZIP in-frame mutations (CEBPAbZIP-inf) is classified within the favorable-risk group by the 2022 European LeukemiaNet (ELN-2022). However, heterogeneous clinical outcomes are still observed in these patients. In this study, we aimed to investigate the mutation profiles and transcriptomic patterns associated with poor outcomes in patients with CEBPAbZIP-inf. One hundred and thirteen CEBPAbZIP-inf patients were identified in a cohort of 887 AML patients homogeneously treated with intensive chemotherapy. Concurrent WT1 or DNMT3A mutations significantly predicted worse survival in AML patients with CEBPAbZIP-inf. RNA-sequencing analysis revealed an enrichment of interferon (IFN) signaling and metabolic pathways in those with a shorter event-free survival (EFS). CEBPAbZIP-inf patients with a shorter EFS had higher expression of IFN-stimulated genes (IRF2, IRF5, OAS2, and IFI35). Genes in mitochondrial complexes I (NDUFA12 and NDUFB6) and V (ATP5PB and ATP5IF1) were overexpressed and were associated with poorer survival, and the results were independently validated in the TARGET AML cohort. In conclusion, concurrent WT1 or DNMT3A mutations and a dysregulated immune and metabolic state were correlated with poor survival in patients with CEBPAbZIP-inf, and upfront allogeneic transplantation may be indicated for better long-term disease control.
| S-EPMC10803338 | biostudies-literature
Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases.
2011-12-31 | GSE32246 | GEO
Project description:CCAAT/enhancer-binding protein alpha (CEBPA) mutations are a favorable prognostic factor in adult acute myeloid leukemia (AML) patients; however, few studies have examined their significance in pediatric AML patients. Here we examined the CEBPA mutation status and clinical outcomes of pediatric AML patients treated in the AML-05 study. We found that 47 (14.9%) of the 315 evaluable patients harbored mutations in CEBPA; 26 cases (8.3%) harbored a single mutation (CEBPA-single) and 21 (6.7%) harbored double or triple mutations (CEBPA-double). After excluding core-binding factor-AML cases, patients harboring CEBPA mutations showed better overall survival (OS; P=0.048), but not event-free survival (EFS; P=0.051), than wild-type patients. Multivariate analysis identified CEBPA-single and CEBPA-double as independent favorable prognostic factors for EFS in the total cohort (hazard ratio (HR): 0.47 and 0.33; P=0.02 and 0.01, respectively). CEBPA-double was also an independent favorable prognostic factor for OS (HR: 0.30; P=0.04). CEBPA-double remained an independent favorable factor for EFS (HR: 0.28; P=0.04) in the normal karyotype cohort. These results suggest that CEBPA mutations, particularly CEBPA-double, are an independent favorable prognostic factor in pediatric AML patients, which will have important implications for risk-stratified therapy.
| S-EPMC4219441 | biostudies-other
Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.
2011-12-31 | E-GEOD-32246 | biostudies-arrayexpress
Project description:BackgroundIn a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect.Design and methodsData from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial.ResultsThe frequencies of mutations were: NPM1, 23%; CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. The genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count.ConclusionsIn elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype 'mutant NPM1 without FLT3-ITD' appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: NCT00151242).
| S-EPMC2625424 | biostudies-literature