演題詳細

一般口演 / Oral Session

一般口演 34 (Oral Session 34) :MDS/MPN:基礎 2

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日程
2013年10月11日(金)
時間
15:25 - 16:25
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
原田 浩徳 (Hironori Harada):1
1:順天堂大学 血液内科
 
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Generation and analysis of a novel model for CMML with acquired expression of c-CBL Q367P

演題番号 : OS-1-174

中田 雄一郎 (Yuichiro Nakata):1、上田 健 (Takeshi Ueda):1、山崎 憲政 (Norimasa Yamasaki):1、長町 安希子 (Akiko Nagamachi):2、田久保 圭誉 (Keiyo Takubo):3、海老原 康広 (Yasuhiro Ebihara):4、真田 昌 (Masashi Sanada):5、小川 誠司 (Seishi Ogawa):5、辻 浩一郎 (Koichiro Tsuji):4、須田 年生 (Toshio Suda):3、稲葉 俊哉 (Toshiya Inaba):2、本田 浩章 (Hiroaki Honda):1

1:Dept. Disease Model, Inst. Rad. Biol. Med., Hiroshima Univ., Japan、2:Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan、3:Department of Cell Differentiation, Keio University、4:Department of Pediatric Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Japan、5:Cancer Genomics Project, The University of Tokyo, Japan

 

c-CBL functions as an E3 ubiquitin ligase and negatively regulates cytokine-mediated signaling. Recently, we identified c-CBL mutations in myelodysplastic syndrome, mainly in chronic myelomonocytic leukemia (CMML). This suggests that dysfunction of c-CBL is implicated in the disease pathogenesis, but the precise molecular mechanism(s) remains elusive. To address this issue and to create an animal model for mutated c-CBL-harboring leukemia, we generated conditional knock-in (cKI) mice that express wild-type c-CBL at steady state and in turn express c-CBL with Q367P mutation upon Cre activation. The cKI mice exhibited leukocytosis with a rapid sustained expansion of myelomonocytic cells with dysplasia, the clinical hallmark of CMML, allowing us to consider the cKI mice as a model for human CMML. Constitutive phospholylation of Akt was observed in long-term hematopoietic stem cells (HSCs) of the cKI mice, indicating that CMML is a stem cell disease. In addition, retrovirus infection to the cKI mice converted CMML to acute leukemia, strongly suggesting that additional somatic event(s) contributes to disease progression. We are currently investigating the molecular pathogenesis of the disease by transcriptome analysis and identifying the genes responsible for disease progression by inverse PCR.

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