title: High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML.
abstract: EVI1 and MEL1 are homolog genes whose transcriptional activations by chromosomal translocations are known in small subsets of leukemia. From gene expression profiling data of 130 Japanese pediatric acute myeloid leukemia (AML) patients, we found that EVI1 and MEL1 were overexpressed in ~30% of patients without obvious translocations of these gene loci, and that their high expression was significantly associated with inferior survival. High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype. On the other hand, high MEL1 expression was detected in myelocytic-lineage (designated as e-M0/M1/M2 subtype) and e-M4/M5 subtype leukemia without MLL rearrangements, and its prognostic association was independent from the subtypes. Because of their subtype-dependent and mutually exclusive expression, a combined evaluation of their high expression enabled a clear distinction of patients with inferior survival (P<0.00001 in event-free survival (EFS) and overall survival (OS)). This association was confirmed by quantitative reverse transcription PCR analysis of an independent cohort of 81 patients (P=0.00017 in EFS, P=0.00028 in OS). We propose that the combined estimation of EVI1 and MEL1 expression will be an effective method to predict the prognosis of pediatric AML.
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Jo
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mitani
authors.affiliation: 1] Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan [2] Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: 1] Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan [2] Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Graduate School of Horticulture, Chiba University, Matsudo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of First Pediatrics, Toho University School of Medicine, Tokyo, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Tsukimoto
authors.affiliation: Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tawa
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taga
authors.affiliation: Human Health Sciences, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: 1] Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan [2] Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan [3] Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ichikawa
mesh_terms: D000293:Adolescent; D019070:Cell Lineage; D002875:Chromosomes / Q000648:ultrastructure; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement; D006801:Humans; D007564:Japan; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011519:Proto-Oncogenes / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C416371:PRDM16 protein, human; D014157:Transcription Factors