title: Recurrent CDC25C mutations drive malignant transformation in FPD/AML.
abstract: Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.
authors.affiliation: 1] Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2].
authors.forename: Akihide
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: 1] Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan [2].
authors.forename: Takashi
authors.initials: T
authors.lastname: Toya
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawazu
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Ayato
authors.initials: A
authors.lastname: Tsukamoto
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Iizuka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Nannya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Hematology, NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Usuki
authors.affiliation: Department of Hematology/Oncology, Gunma Children's Medical Center, 779 Simohakoda, Kitaakebonocho, Shibukawa-shi, Gunma 377-8577, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Hirosaki University, 53 Honmachi, Hirosaki-shi, Aomori 036-8563, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.affiliation: Department of Hematology and Oncology, University of Yamanashi, 1110 Simokawakita, Chuou-shi, Yamanashi 409-3898, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kirito
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D001791:Blood Platelet Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004249:DNA Damage; D050989:GATA2 Transcription Factor / Q000235:genetics; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D010375:Pedigree; D013921:Thrombocytopenia / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C493728:RUNX1 protein, human; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases