title: Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts.
abstract: The percentage of myeloperoxidase (MPO)-positive blast cells is a simple and highly significant prognostic factor in AML patients. It has been reported that the high MPO group (MPO-H), in which >50% of blasts are MPO activity positive, is associated with favorable karyotypes, while the low MPO group (≤50% of blasts are MPO activity positive, MPO-L) is associated with adverse karyotypes. The MPO-H group shows better survival even when restricted to patients belonging to the intermediate chromosomal risk group or those with a normal karyotype. It has recently been shown that genotypes defined by the mutational status of NPM1, FLT3, and CEBPA are associated with treatment outcome in patients with cytogenetically normal AML. In this study, we aimed to evaluate the relationship between MPO positivity and gene mutations found in normal karyotypes. Sixty AML patients with normal karyotypes were included in this study. Blast cell MPO positivity was assessed in bone marrow smears stained for MPO. Associated genetic lesions (the NPM1, FLT3-ITD, and CEBPA mutations) were studied using nucleotide sequencing. Thirty-two patients were in the MPO-L group, and 28 patients in the MPO-H group. FLT3-ITD was found in 11 patients (18.3%), NPM1 mutations were found in 19 patients (31.7%), and CEBPA mutations were found in 11 patients (18.3%). In patients with CEBPA mutations, the carrying two simultaneous mutations (CEBPA (double-mut)) was associated with high MPO expression, while the mutant NPM1 without FLT3-ITD genotype was not associated with MPO activity. Both higher MPO expression and the CEBPA (double-mut) genotype appeared to be associated with improved overall survival after intensive chemotherapy. Further studies are required to determine the importance of blast MPO activity as a prognostic factor, especially in CEBPA wild-type patients with a normal karyotype.
authors.affiliation: Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tominaga-Sato
authors.affiliation: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. tsushima@nagasaki-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsushima
authors.affiliation: Department of Internal Medicine, Nagasaki National Medical Center, Ohmura, Nagasaki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Itonaga
authors.affiliation: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Imaizumi
authors.affiliation: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Imanishi
authors.affiliation: Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Iwanaga
authors.affiliation: Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Taguchi
authors.affiliation: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Internal Medicine, Nagasaki National Medical Center, Ohmura, Nagasaki, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Hematology, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hata
authors.affiliation: Division of Hematology, Sasebo City General Hospital, Sasebo, Nagasaki, Japan.
authors.forename: Yukiyoshi
authors.initials: Y
authors.lastname: Moriuchi
authors.affiliation: School of Health Sciences, University of the Ryukyus, Okinawa, Nishihara, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kuriyama
authors.affiliation: Division of Functional Genomics, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.affiliation: Department of Hematology, Japanese Red-Cross Nagasaki Atomic Bomb Hospital, Nagasaki, Nagasaki, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Tomonaga
authors.affiliation: Department of Hematology and Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyazaki
mesh_terms: D001752:Blast Crisis; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D009195:Peroxidase / Q000235:genetics*; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D009195:Peroxidase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3