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  • 1
    Keywords: CELLS ; CELL ; Germany ; KINASE ; THERAPY ; DEATH ; RISK ; GENE ; GENES ; PROTEIN ; PATIENT ; TRANSPLANTATION ; BINDING ; ASSOCIATION ; ALPHA ; TRIAL ; TRIALS ; AGE ; MUTATION ; leukemia ; MUTATIONS ; HOMOLOG ; ONCOGENE ; OUTCOMES ; STEM-CELL TRANSPLANTATION ; Ras ; ACUTE MYELOGENOUS LEUKEMIA ; STUDY-GROUP ULM ; BINDING PROTEIN ; ADULT ; ADULTS ; THERAPIES ; INTERNAL TANDEM DUPLICATION ; methods ; USA ; normal karyotype ; GROUP-B ; viral ; MEDICINE ; CLINICAL-OUTCOMES ; NRAS ; YOUNGER ADULTS ; CEBPA MUTATIONS ; FAVORABLE PROGNOSTIC-SIGNIFICANCE ; KINASE DOMAIN MUTATIONS ; NUCLEOPHOSMIN NPM1
    Abstract: Background: Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein (alpha) gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients. Methods: We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation. Results: A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. Conclusions: Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML
    Type of Publication: Journal article published
    PubMed ID: 18450602
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  • 2
    Keywords: CANCER ; TARGETS ; TUMOR-SUPPRESSOR ; GROUP-B ; AML ; MICRORNA ; CEBPA MUTATIONS ; SIGNATURES ; miR-34a ; MONOSOMAL KARYOTYPE
    Abstract: Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-nniR-34a axis in a large cohort of CK-AML with known TP53 status (TP53(altere)d, n = 57; Tp53(unaltered), n =31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and nniR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53(unaltered) CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53(biallelic altered) CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53(biallelic altered) cell lines treated with 15-deoxy-Delta(12,14)-prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in Tp53(altered) CK-AML.
    Type of Publication: Journal article published
    PubMed ID: 22810507
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  • 3
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; CELL ; Germany ; GENE ; MARKER ; prognosis ; polymorphism ; single nucleotide polymorphism ; TRIAL ; AGE ; MUTATION ; SNP ; leukemia ; MARKERS ; MUTATIONS ; HIGH-RISK ; GLIOMAS ; GENE-MUTATIONS ; STUDY-GROUP ULM ; ONCOLOGY ; overall survival ; MYELOID-LEUKEMIA ; PROGNOSTIC-FACTOR ; ALLELES ; methods ; PREDICTS ; STEM ; GROUP-B ; outcome ; IDH1 ; CODON 132 ; single nucleotide ; NUCLEOPHOSMIN ; clinical oncology ; AML STUDY-GROUP ; YOUNGER ADULTS 16
    Abstract: Purpose We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers. Patients and Methods IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified. Results IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3-internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles. Conclusion IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML
    Type of Publication: Journal article published
    PubMed ID: 20368538
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