Recurrent CDC25C mutations drive malignant transformation in FPD/AML

Akihide Yoshimi, Takashi Toya, Masahito Kawazu, Toshihide Ueno, Ayato Tsukamoto, Hiromitsu Iizuka, Masahiro Nakagawa, Yasuhito Nannya, Shunya Arai, Hironori Harada, Kensuke Usuki, Yasuhide Hayashi, Etsuro Ito, Keita Kirito, Hideaki Nakajima, Motoshi Ichikawa, Hiroyuki Mano and Mineo Kurokawa ()
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Akihide Yoshimi: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Takashi Toya: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Masahito Kawazu: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Toshihide Ueno: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Ayato Tsukamoto: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Hiromitsu Iizuka: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Masahiro Nakagawa: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Yasuhito Nannya: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Shunya Arai: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Hironori Harada: Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan
Kensuke Usuki: NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
Yasuhide Hayashi: Gunma Children's Medical Center, 779 Simohakoda, Kitaakebonocho, Shibukawa-shi, Gunma 377-8577, Japan
Etsuro Ito: Graduate School of Medicine, Hirosaki University, 53 Honmachi, Hirosaki-shi, Aomori 036-8563, Japan
Keita Kirito: University of Yamanashi, 1110 Simokawakita, Chuou-shi, Yamanashi 409-3898, Japan
Hideaki Nakajima: Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan
Motoshi Ichikawa: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Hiroyuki Mano: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Mineo Kurokawa: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5770

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