title: ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis.
abstract: ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.|Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
authors.forename: Genki
authors.identifier: 0000-0003-4000-0753
authors.initials: G
authors.lastname: Yamato
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.|Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
authors.forename: Yusuke
authors.identifier: 0000-0001-7271-3454
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.|Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Okubo
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Okuno
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, St. Marianna University School of Medicine Hospital, Kanagawa, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Division of Pediatrics, Department of Reproductive and Developmental Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritake
authors.affiliation: Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kiyokawa
authors.affiliation: Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: Myoung-Ja
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sotomatsu
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Pediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Tawa
authors.affiliation: Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.|Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan.|Director General, Japanese Red Cross Gunma Blood Center, Gunma, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics*; D015996:Survival Rate; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C107844:AML1-ETO fusion protein, human; C473949:ASXL1 protein, human; C484295:ASXL2 protein, human; D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins