演題詳細

一般口演 / Oral Session

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

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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
 
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Recurrent somatic SETBP1 mutations in myeloid neoplasms

演題番号 : OS-1-165

昆 彩奈 (Ayana Kon):1,2、牧島 秀樹 (Hideki Makishima):3、吉田 健一 (Kenichi Yoshida):1,2、Nhu Nguyen:4、真田 昌 (Masashi Sanada):1,2、奥野 友介 (Yusuke Okuno):1,5、高橋 真理子 (Mariko Takahashi):1、白石 友一 (Yuichi Shiraishi):6、永田 安伸 (Yasunobu Nagata):1,2、千葉 健一 (Kenichi Chiba):6、村松 秀城 (Hideki Muramatsu):5、小島 勢二 (Seiji Kojima):5、宮野 悟 (Satoru Miyano):6、Lee-Young Shih:7、Yang Du:4、小川 誠司 (Seishi Ogawa):1,2、Jaroslaw P. Maciejewski:3

1:Cancer Genomics Project, The University of Tokyo, Tokyo, Japan、2:Dept. Pathology and Tumor Biology, Kyoto University, Kyoto, Japan、3:Dept. Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA、4:Dept. Pediatrics, Uniformed Services Univ. of the Health Sciences, Bethesda, MD, USA、5:Dept. Pediatrics, Nagoya University, Nagoya, Japan、6:Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan、7:Division of Hematology-Oncology, Dept. Internal Medicine, Chung Gung Memorial Hospital

 

The pathogenesis of leukemic progression in myeloid neoplasms includes stepwise acquisition of genetic lesions, whose targets are largely unknown. So we performed whole exome analysis in 20 myeloid neoplasms and identified novel recurrent mutations in SETBP1. Targeted resequencing in 727 samples from various myeloid neoplasms confirmed frequent SETBP1 mutations involving D868, G870, I871 and D880, in 53 cases that were identical to germ-line mutations reported in Schinzel-Giedion syndrome. SETBP1 mutations were associated with sAML, CMML phenotype, higher age, -7/del(7q) and poor prognosis. Analysis of serial samples indicated that SETBP1 mutations were acquired during leukemic evolution. Transduction of Setbp1 mutants led to immortalization of myeloid progenitors and proliferated faster than cells with WT Setbp1, supporting their gain-of-function nature. Both WT and mutant Setbp1-immortalized cells expressed comparable levels of Hoxa9 and Hoxa10 mRNAs, suggesting that HOXA9 and HOXA10 are likely their functional targets. Consistent with the previous report, western blot analysis of Jurkat cells transduced with WT and mutant SETBP1 revealed that mutant SETBP1 are expressed higher than WT SETBP1, while having similar mRNA levels, suggesting that the mutations could increase protein stability. Further, WT SETBP1 levels, but not mutant SETBP1 levels, increased by adding proteasome inhibitor, indicating that WT protein is more prone to degradation by proteasome. We will discuss the mechanism in which SETBP1 mutations lead to gain of function and myeloid leukemic transformation.

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