演題詳細

一般口演 / Oral Session

【E】一般口演 33 (Oral Session 33) :MDS/MPN:Basic Research 1

print

日程
2013年10月11日(金)
時間
14:25 - 15:25
会場
第14会場 / Room No.14 (札幌市教育文化会館 3F 研修室305)
座長・司会
桐戸 敬太 (Keita Kirito):1
1:Department of Hematology, University of Yamanashi, Japan
 
前へ戻る

Clonal and mutational evolution reveals genetic mechanisms of leukemia transformation of FPD/AML

演題番号 : OS-1-167

吉見 昭秀 (Akihide Yoshimi):1、遠矢 嵩 (Takashi Toya):1、飯塚 浩光 (Hiromitsu Iizuka):1、荒井 俊也 (Shunya Arai):1、中川 正宏 (Masahiro Nakagawa):1、河津 正人 (Masahito Kawazu):2、市川 幹 (Motoshi Ichikawa):1、桐戸 敬太 (Keita Kirito):3、間野 博行 (Hiroyuki Mano):4、黒川 峰夫 (Mineo Kurokawa):1

1:Department of Hematology and Oncology, the University of Tokyo、2:Department of Medical Genomics, the University of Tokyo、3:Department of Hematology and Oncology, University of Yamanashi、4:Department of Biochemistry and Molecular Biology, The University of Tokyo

 

FPD/AML is an autosomal dominant disorder characterized by platelet defects with a predisposition for the development of hematological malignancies, and inherited RUNX1 mutation is the cause of this disease. Given that only 40 % of FPD/AML patients develop leukemia, RUNX1 mutation is not sufficient to induce malignant transformation. To identify additional genetic alterations, we utilized whole exome sequencing in two patients with FPD/AML who developed MDS or myelofibrosis followed by AML. We identified 12 and 10 somatically acquired nonsynonymous mutations in these patients, respectively. Interestingly, the two patients had common CDC25C mutation at codon 234 (D234G), and CDC25C_H437N somatic mutation was found in another FPD/AML patient with AML. CDC25C is a phosphatase that mediates cellular entry into mitosis and prevents premature mitosis in response to DNA damage at the G2 checkpoint. In mutated CDC25Cs, binding capacity with C-TAK1 and 14-3-3 protein was reduced, leading to decreased phosphorylation status of CDC25C at Ser216. As a consequence, mitosis entry was enhanced in cells transduced with mutated CDC25Cs, which was exaggerated by radiation-induced DNA damage. These results suggested that mutated CDC25C enhances cellular entry into mitosis and establishes foundation for the development of aggressive malignancy in FPD/AML. Furthermore, next generation sequencing enabled us to estimate clonal evolution and devolution during leukemic transformation. Results of single cell genomic sequencing supported the evolution model that was predicted by the exome sequencing.

前へ戻る