Format

Send to

Choose Destination
Nat Commun. 2014 Aug 27;5:4770. doi: 10.1038/ncomms5770.

Recurrent CDC25C mutations drive malignant transformation in FPD/AML.

Author information

1
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].
2
Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
3
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
4
Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
5
Department of Hematology, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan.
6
Department of Hematology, NTT Medical Center Tokyo, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan.
7
Department of Hematology/Oncology, Gunma Children's Medical Center, 779 Simohakoda, Kitaakebonocho, Shibukawa-shi, Gunma 377-8577, Japan.
8
Department of Pediatrics, Graduate School of Medicine, Hirosaki University, 53 Honmachi, Hirosaki-shi, Aomori 036-8563, Japan.
9
Department of Hematology and Oncology, University of Yamanashi, 1110 Simokawakita, Chuou-shi, Yamanashi 409-3898, Japan.
10
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.

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.

PMID:
25159113
DOI:
10.1038/ncomms5770
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center