title: High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.
abstract: Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Division of Clinical Research Planning, Department of Development Strategy, Centre for Clinical Research and Development, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Yamato
authors.affiliation: Department of Paediatrics, Yokohama City University Hospital, Yokohama, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Tanoshima
authors.affiliation: Division of Genetics, National Cancer Centre Research Institute, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Leukaemia and Lymphoma, Children's Cancer Centre, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
authors.forename: Myoung-Ja
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Paediatrics, Okayama University Hospital, Okayama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sotomatsu
authors.affiliation: Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Paediatrics, Shiga University of Medical Science, Ohtsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Paediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Tawa
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; C416371:PRDM16 protein, human; D014157:Transcription Factors; C093350:nuclear pore complex protein 98; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: AML; FLT3-ITD; KMT2A-PTD; NUP98-NSD1; PRDM16; gene expression