Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML.
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.
Barjesteh van Waalwijk van Doorn-Khosrovani
Sahar
S
Institute of Hematology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Erpelinck
Claudia
C
Meijer
Joost
J
van Oosterhoud
Susanna
S
van Putten
Wim L J
WL
Valk
Peter J M
PJ
Berna Beverloo
H
H
Tenen
Daniel G
DG
Löwenberg
Bob
B
Delwel
Ruud
R
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D016368:Frameshift Mutation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007621:Karyotyping; D016350:Leucine Zippers / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011379:Prognosis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012074:Remission Induction; D012306:Risk; D012307:Risk Factors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D016019:Survival Analysis
D022763:CCAAT-Enhancer-Binding Protein-alpha; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm