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論文 |
論文
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Nishimura, Riki ; Takita, Junko ; Sato-Otsubo, Aiko ; Kato, Motohiro ; Koh, Katsuyoshi ; Hanada, Ryoji ; Tanaka, Yukichi ; Kato, Keisuke ; Maeda, Daichi ; Fukayama, Masashi ; Sanada, Masashi ; Hayashi, Yasuhide ; Ogawa, Seishi ; 前田, 大地
概要:
金沢大学医薬保健研究域医学系<br />Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes,
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embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited near-diploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS. © 2013 Japanese Cancer Association.
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論文 |
論文
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Katagiri, Takamasa ; Sato-Otsubo, Aiko ; Kashiwase, Koichi ; Morishima, Satoko ; Sato, Yusuke ; Mori, Yuka ; Kato, Motohiro ; Sanada, Masashi ; Morishima, Yasuo ; Hosokawa, Kohei ; Sasaki, Yumi ; Ohtake, Shigeki ; Ogawa, Seishi ; Nakao, Shinji
概要:
Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progeni
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tors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-Aexpression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLAalleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes"hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant autoantigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA. © 2011 by The American Society of Hematology.
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