Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML
| Autor: | van Putten Wl, Peter J. M. Valk, Ruud Delwel, Meijer J, Erpelinck C, Berna Beverloo H, Barjesteh van Waalwijk van Doorn-Khosrovani S, Bob Löwenberg, Daniel G. Tenen, van Oosterhoud S |
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| Přispěvatelé: | Hematology, Molecular Genetics |
| Rok vydání: | 2003 |
| Předmět: |
Adult
Male Risk DNA Complementary Adolescent DNA Mutational Analysis Molecular Sequence Data Biology Disease-Free Survival Frameshift mutation Risk Factors Enhancer binding CEBPA medicine CCAAT-Enhancer-Binding Protein-alpha Humans Life Tables Amino Acid Sequence RNA Messenger RNA Neoplasm Allele Frameshift Mutation Survival analysis BAALC Alleles Leucine Zippers Binding Sites Sequence Homology Amino Acid Gene Expression Regulation Leukemic Hazard ratio Remission Induction Hematology DNA Neoplasm Middle Aged medicine.disease Prognosis Molecular biology Survival Analysis Neoplasm Proteins Protein Structure Tertiary Leukemia Mutagenesis Insertional Leukemia Myeloid Karyotyping Acute Disease Cancer research Neoplastic Stem Cells Female Sequence Alignment |
| Zdroj: | Hematology Journal, 4, 31-40. Ferrata Storti Foundation |
| ISSN: | 1466-4860 |
| Popis: | The CCAAT/enhancer binding protein alpha is an essential transcription factor for granulocytic differentiation. Recent studies reported N- and C-terminal CEBPA mutations in approximately 7% of acute myeloid leukaemia (AML) patients. C-terminal mutations are usually in-frame and occur in the basic-leucine zipper (bZIP) domain, resulting in deficient DNA binding. Using a rapid PCR approach, we screened for bZIP mutations and determined the prognostic value of these mutations in a cohort of 277 de novo AMLs. In addition, we set out to quantify CEBPA mRNA levels by 'real-time' PCR using TaqMan technology. In-frame insertions were observed in 12 (4.3%) cases. All cases with mutations carried an intermediate-risk karyotype and all but one belonged to M1 or M2 FAB class. Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA. These two mutations were always found in different alleles. Event-free survival (EFS) and overall survival (OS) of patients with CEBPA mutations were significantly increased (P=0.02 and 0.03, respectively) in comparison to the patients lacking these mutations. Mutations were associated with a significantly reduced hazard ratio for death (OS: HR=0.35, P=0.04) and failure (EFS: no CR, death in CR or relapse, HR=0.37, P=0.03). This favourable hazard ratio was maintained after adjustment for cytogenetic risk, FLT3-ITD and CEBPA expression levels in multivariable analysis. In contrast, low CEBPA expression in AML with intermediate-risk karyotype (n=6) seemed to be associated with poor prognosis (not significant). By including this newly developed PCR assay, we define a subgroup of good-risk patients within the heterogeneous intermediate-risk group of AML. |
| Databáze: | OpenAIRE |
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