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.
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We thank the following institutions and investigators that participated in the AML99 and AML-05 studies conducted by Japanese Childhood AML Cooperative Study Group and Japanese Pediatric Leukemia/Lymphoma Study Group, respectively: Kazuko Hamamoto, Department of Pediatrics, Hiroshima Red Cross Hospital; Ryoji Hanada, Department of Hematology/Oncology, Saitama Children’s Medical Center; Masue Imaizumi, Department of Hematology/Oncology, Miyagi Prefectural Children’s Hospital; Shotaro Iwamoto, Department of Pediatrics, Mie University School of Medicine; Hisato Kigasawa, Department of Hematology, Kanagawa Children’s Medical Center; Akitoshi Kinoshita, Department of Pediatrics, St Marianna University School of Medicine; Ryoji Kobayashi, Department of Pediatrics, Hokkaido University School of Medicine; Katsuyoshi Koh, Department of Hematology/Oncology, Saitama Children’s Medical Center; Yoshiyuki Kosaka, Department of Hematology and Oncology, Hyogo Children’s Hospital; Kazuko Kudo, Department of Pediatrics, Nagoya University Graduate School of Medicine; Akira Morimoto, Department of Pediatrics, Kyoto Prefectural University of Medicine; Hiroshi Moritake, Division of Pediatrics, Department of Reproductive and Developmental Medicine, Faculty of Medicine, University of Miyazaki; Hideki Nakayama, Department of Pediatrics, Hamanomachi Hospital; Akira Ohara, Department of First Pediatrics, Toho University School of Medicine; Akira Shimada, Department of Pediatrics, Okayama University; Hiroyuki Takahashi, Department of Pediatrics, Saiseikai Yokohama City Southern Hospital; Kiminori Terui, Department of Pediatrics, Hirosaki University Graduate School of Medicine; Masahiro Tsuchida, Department of Pediatrics, Ibaraki Children’s Hospital; Shigeru Tsuchiya, Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University; and Hiromasa Yabe, Department of Pediatrics, Tokai University School of Medicine. This work was supported by a Grant-in-Aid for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare of Japan; the programme for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan; and Grants-in-Aid for Scientific Research (B, C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Y Hayashi, TY and HI designed and organized this study; AJ, SM, NS, Y Hara and HI performed molecular analysis; Y Hayashi, IT, AT, KH, DT, TT and SA collected patient samples and clinical data; AJ, HT and HI analyzed and interpreted data; and AJ and HI wrote the manuscript.
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Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
Genes, Chromosomes and Cancer (2017)