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, Mineo Kurokawa

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish
Article number4770
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014 Aug 27

Fingerprint

leukemias
mutations
Platelets
platelets
Acute Myeloid Leukemia
Blood Platelets
disorders
Mutation
progressions
Hematologic Neoplasms
G2 Phase Cell Cycle Checkpoints
Germ-Line Mutation
Biomarkers
pathogenesis
biomarkers
DNA Damage
Leukemia
genes
Clone Cells
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Yoshimi, A., Toya, T., Kawazu, M., Ueno, T., Tsukamoto, A., Iizuka, H., ... Kurokawa, M. (2014). Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nature Communications, 5, [4770]. https://doi.org/10.1038/ncomms5770

Recurrent CDC25C mutations drive malignant transformation in FPD/AML. / Yoshimi, Akihide; Toya, Takashi; Kawazu, Masahito; Ueno, Toshihide; Tsukamoto, Ayato; Iizuka, Hiromitsu; Nakagawa, Masahiro; Nannya, Yasuhito; Arai, Shunya; Harada, Hironori; Usuki, Kensuke; Hayashi, Yasuhide; Ito, Etsuro; Kirito, Keita; Nakajima, Hideaki; Ichikawa, Motoshi; Mano, Hiroyuki; Kurokawa, Mineo.

In: Nature Communications, Vol. 5, 4770, 27.08.2014.

Research output: Contribution to journalArticle

Yoshimi, A, Toya, T, Kawazu, M, Ueno, T, Tsukamoto, A, Iizuka, H, Nakagawa, M, Nannya, Y, Arai, S, Harada, H, Usuki, K, Hayashi, Y, Ito, E, Kirito, K, Nakajima, H, Ichikawa, M, Mano, H & Kurokawa, M 2014, 'Recurrent CDC25C mutations drive malignant transformation in FPD/AML', Nature Communications, vol. 5, 4770. https://doi.org/10.1038/ncomms5770
Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nature Communications. 2014 Aug 27;5. 4770. https://doi.org/10.1038/ncomms5770
Yoshimi, Akihide ; Toya, Takashi ; Kawazu, Masahito ; Ueno, Toshihide ; Tsukamoto, Ayato ; Iizuka, Hiromitsu ; Nakagawa, Masahiro ; Nannya, Yasuhito ; Arai, Shunya ; Harada, Hironori ; Usuki, Kensuke ; Hayashi, Yasuhide ; Ito, Etsuro ; Kirito, Keita ; Nakajima, Hideaki ; Ichikawa, Motoshi ; Mano, Hiroyuki ; Kurokawa, Mineo. / Recurrent CDC25C mutations drive malignant transformation in FPD/AML. In: Nature Communications. 2014 ; Vol. 5.
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