title: The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML.
abstract: HOXA4 gene expression is a predictor for outcome in normal karyotypic acute myeloid leukaemia (AML) patients. Given that Meis1 is a co-factor for Hox genes, we hypothesized that the combined expression of HOXA4 and MEIS1 might add prognostic information in these patients. When diagnostic samples from 246 AML patients were divided into three main groups based on gene expression levels of HOXA4 combined with MEIS1 we found that within the group of patients exhibiting low levels of HOXA4, those with a high expression of MEIS1 had a significantly worse outcome than those exhibiting low MEIS1 expression (P = 0.025). Moreover, this prediction was independent of cytogenetics, mutational status of the NPM1 and FLT3 genes as well as upon WBC and age. To evaluate the possible contribution of regulatory events underlying these observations, 157 patient samples were subjected to promoter hypermethylation analysis. We observed that 77% were HOXA4- and 15%MEIS1 hypermethylated and that this epigenetic alteration was highly correlated to the gene expression level (MEIS1: P = 0.001; HOXA4: P = 0.007). Finally, we found a higher expression level and a higher frequency of hypermethylation of HOXA4 among patients with NPM1 mutations. In conclusion, our data show that the combination of low HOXA4 and low MEIS1 gene expression is a favourable predictor for outcome in all AML patients and that the expression levels are governed by the methylation state of these genes.
authors: Department of Haematology, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors: Mike
authors: M
authors: Zangenberg
authors: Lykke
authors: L
authors: Grubach
authors: Anni
authors: A
authors: Aggerholm
authors: Trine
authors: T
authors: Silkjaer
authors: Caroline
authors: C
authors: Juhl-Christensen
authors: Charlotte Guldborg
authors: CG
authors: Nyvold
authors: Eigil
authors: E
authors: Kjeldsen
authors: Hans Beier
authors: HB
authors: Ommen
authors: Peter
authors: P
authors: Hokland
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D015996:Survival Rate; D014157:Transcription Factors
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000090243:Nucleophosmin; C073547:HOXA4 protein, human