ＳＮＰアレイとメチル化アレイを用いたＴ細胞型急性リンパ性白血病の統合的遺伝子解析

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23591560
• Research Institution: Gunma Institute of Public Health and Environmental Sciences
• Principal Investigator: 朴 明子 群馬県衛生環境研究所, 研究企画係, 研究員 (50450375)
• Co-Investigator(Kenkyū-buntansha): 林 泰秀 群馬県衛生環境研究所, その他部局等, 研究員 (30238133) ; 外松 学 群馬県衛生環境研究所, その他部局等, 研究員 (70251113) ; 大木 健太郎 群馬県衛生環境研究所, その他部局等, 研究員 (50400966)
• Keywords: 遺伝子 / ゲノム / 癌 / マイクロアレイ

Research Abstract

小児T細胞型急性リンパ性白血病(T-ALL)のJACLS 55例の検体をSNPアレイ解析を行ない、昨年度までにホモ欠失やuniparental disomy（UPD）から11p13のWT1遺伝子、4qのLEF1遺伝子、およびNOTCH1経路に関連する遺伝子を含む複数の新規遺伝子の変異解析と臨床的解析を行い、治療成績の向上とT-ALLの病態解明を行ってきた。またT細胞のみならずB細胞の分化にも関与しているIL7R遺伝子につき、JACLSのT-ALL登録 55例で研究を行い、55例中４例(7.2%)にIL7Rの異常がみられ、これらは再発がなく、予後良好であることが示唆された。TCCSGのT-ALL 60例を加え臨床像との関係を詳細に検討したが、ほぼJACLSの結果と同様であった。さらにＳＮＰアレイを用いてT-ALLとT-NHLの発症と進展に関与する新規遺伝子の抽出を行い、新たにBCL11B遺伝子等の新規遺伝子をみいだし、BCL11B遺伝子の変異と臨床像との関係を検討中である。
今年度はさらに、再発症例６例を含むT-ALL 16例において全エクソーム解析を行った。平均19個の体細胞変異が抽出され、再発例と非再発例の変異数は同等であった。NOTCH1変異が最も多く、全体の56%に認められ、再発例に多くを認めた(87%)。FBXW7変異は32%に認められたが、その他３症例以上で重複する遺伝子変異は認めなかった。近年CNOT3変異は小児に比し、成人T-ALLIに多い事が報告されたが、今回の検討では２例に認められた。NT5C2変異は再発特異的な変異として報告されたが、再発６例のうち１例の再発検体のみに認められた。それぞれの再発例において初発時と再発時に共有する遺伝子変異が認められた。今後さらに多数例で再発特異的な変異を検討することにより再発クローン発生の病態解明に貢献すると思われる。

Research Products

• [Journal Article] Mutations of the GATA2 and CEBPA genes in paediatric acute myeloid leukaemia (2014)
  • Author(s): Shiba N, Funato M, Ohki K, Park MJ, Mizushima Y, Adachi S, Kobayashi M, Kinoshita A, Sotomatsu M, Arakawa H, Tawa A, Horibe K, Tsukimoto I, Hayashi Y.
  • Journal Title: Br J Haematol Volume: 164 Pages: 142-159
  • DOI: 10.1111/bjh.12559
  • Peer Reviewed
• [Journal Article] Significance of CD66c expression in childhood acute lymphoblastic leukemia. (2014)
  • Author(s): Kiyokawa N, Iijima K, Tomita O, Miharu M, Hasegawa D, Kobayashi K, Okita H, Kajiwara M, Shimada H, Inukai T, Makimoto A, Fukushima T, Nanmoku T, Koh K, Manabe A, Kikuchi A, Sugita K, Fujimoto J, Hayashi Y, Ohara A.
  • Journal Title: Leuk Res. Volume: 38 Pages: 42-48
  • DOI: 10.1016/j.leukres
  • Peer Reviewed
• [Journal Article] Liver disease is frequently observed in Down syndrome patients with transient abnormal myelopoiesis. (2014)
  • Author(s): Park MJ, Sotomatsu M, Ohki K, Arai K, Maruyama K, Kobayashi T, Nishi A, Sameshima K, Takagi T, Hayashi Y.
  • Journal Title: Int J Hematol Volume: 99 Pages: 154-161
  • DOI: 10.1007/s12185-013-1487-5.
  • Peer Reviewed
• [Journal Article] SETBP1 mutations in juvenile myelomonocytic leukaemia and myelodysplastic syndrome but not in paediatric acute myeloid leukaemia. (2014)
  • Author(s): Shiba N, Ohki K, Park MJ, Sotomatsu M, Kudo K, Ito E, Sako M, Arakawa H, Hayashi Y.
  • Journal Title: Br J Haematol Volume: in press Pages: in press
  • DOI: 10.1111/bjh.12595
  • Peer Reviewed
• [Journal Article] NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia (2013)
  • Author(s): Shiba N, Ichikawa H, Taki T, Park MJ, Jo A, Mitani S, Kobayashi T, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 52 Pages: 683-693
  • DOI: 10.1002/gcc.22064
  • Peer Reviewed
• [Journal Article] Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome (2013)
  • Author(s): Toki T, Kanezaki R, Kobayashi E, Kaneko H, Suzuki M, Wang R, Terui K, Kanegane H, Maeda M, Endo M, Mizuochi T, Adachi S, Hayashi Y, Yamamoto M, Shimizu R, Ito E.
  • Journal Title: Blood Volume: 121 Pages: 3181-3184
  • DOI: 10.1182/blood-2012-01-405746
  • Peer Reviewed
• [Journal Article] Cytomegalovirus retinitis during maintenance therapy for T-cell acute lymphoblastic leukemia (2013)
  • Author(s): Wakai K, Sano H, Shimada A, Shiozawa Y, Park MJ, Sotomatsu M, Yanagisawa R, Koike K, Kozawa K, Ryo A, Tsukagoshi H, Kimura H, Hayashi Y.
  • Journal Title: J Pediatr Hematol Oncol Volume: 35 Pages: 162-163
  • DOI: 10.1097/MPH.0b013e318279e920
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders. (2013)
  • Author(s): Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, et al.
  • Journal Title: Nat Genet. Volume: 45 Pages: 1293-1299
  • DOI: 10.1038/ng.2759.
  • Peer Reviewed
• [Journal Article] WT1 mutation in pediatric patients with acute myeloid leukemia: a report from the Japanese Childhood AML Cooperative Study Group. (2013)
  • Author(s): Sano H, Shimada A, Tabuchi K, Taki T, Murata C, Park MJ, Ohki K, Sotomatsu M, Adachi S, Tawa A, Kobayashi R, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y.
  • Journal Title: Int J Hematol Volume: 98 Pages: 437-445
  • DOI: 10.1007/s12185-013-1409-6.
  • Peer Reviewed
• [Presentation] Whole-Exome Resequencing Identifies Somatic Mutations Of BCOR and BCORL1 Transcriptional Corepressor Genes and Major Cohesin Complex Component Genes In Pediatric Acute Myeloid Leukemia. (2013)
  • Author(s): Shiba N, Ohki K, Nagata Y, Kon A, Okuno Y,Shiraishi Y, Kato M, Park MJ, Ohki K, Takita J, Kanazawa T, Kudo K, Ito E, Sanada M, Tomizawa D, Tawa A, Adachi S, Miyano S, Ogawa S, Hayashi Y.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] Low Frequency and Poor Prognosis Of MLL-Partial Tandem Duplications In Pediatric Acute Myeloid Leukemia Using MLPA Method: The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Trial. (2013)
  • Author(s): Ohki K, Park MJ, Sano H, Hara Y, Shiba N, Tomizawa D, Taga T, Moriya Saito A, Fujimoto J, Tawa A, Horibe K, Adachi S, Hayashi Y.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] Whole Exome Sequencing Reveals Clonal Evolution Pattern and Driver Mutations Of Relapsed Pediatric AML. (2013)
  • Author(s): Yoshida K, Shiba N, Shiraishi Y, Shimada A, Terui K, Kato M, Okuno Y, Nagata Y, Kon A, Yoshizato T, Matsunawa, M, Chiba K, Tanaka H, Sanada M, Miyano S, Ito E, Hayashi Y, Ogawa S.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] Comprehensive Fusion Gene Analysis Of Pediatric Non-Down Syndrome Acute Megakaryoblasitc Leukemia. (2013)
  • Author(s): Hara Y, Shiba n, Ohki K, Park MJ, Tomizawa D, Taga T, Saito A, Fujimoto J, Arakawa H, Tawa A, Horibe K, Adachi S, Hayashi Y.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] An Analysis Of Ph-Like ALL In Japanese Patients. (2013)
  • Author(s): Kiyokawa N, Iijima K, Yoshihara H, Ohki K, Kato M, Fukushima T, Kikuchi A, Fujimoto J, Hayashi Y, Koh K, Manabe A, Ohara A.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] CSF3R Gene Mutations In Myeloid Malignancy Of Childhood. (2013)
  • Author(s): Sano H, Ohki K, Park MJ, Hara Y, Shiba N, Tomizawa D, Taga T, Moriya Saito A, Fujimoto J, Tawa A, Horibe K, Adachi S, Hayashi Y.
  • Organizer: 55rd Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans
  • Year and Date: 20131207-20131210
• [Presentation] 小児急性骨髄性白血病におけるGATA2遺伝子変異の解析.
  • Author(s): 柴 徳生, 朴 明子, 舩戸道徳, 小林正夫, 木下明俊, 足立壮一, 荒川浩一, 多和昭雄, 月本一郎, 林 泰秀.
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
• [Presentation] NUP98-NSD1融合遺伝子陽性例は小児急性骨髄性白血病において予後不良である.
  • Author(s): 原 勇介, 柴 徳生, 嶋田 明, 工藤寿子, 富澤大輔, 多賀 崇, 多和昭雄, 荒川浩一, 足立壮一, 林 泰秀.
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
• [Presentation] 小児B型前駆細胞型ALLにおけるCRLF2高発現例の特徴：TCCSG-ALL研究.
  • Author(s): 大木健太郎, 朴 明子, 柴 徳生, 清河信敬, 康 勝好, 花田良二, 真部 淳, 菊地 陽, 小原 明, 林 泰秀.
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
• [Presentation] 染色体異常を伴ったダウン症合併TAMとAMKLの遺伝子解析.
  • Author(s): 朴 明子, 大木健太郎, 新井 心, 外松 学, 林 泰秀.
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島
• [Presentation] NUP98-MSD1 gene fusion is a strong poor prognostic factor in pediatric AML.
  • Author(s): Hara Y, Shiba N, Shimada A, Kudo K, Tomizawa D, Taga T, Horibe K, Adachi S, Arakawa H, Tawa A, Hayashi Y.
  • Organizer: 45th Congress of the International Society of Pediatric Oncology.
  • Place of Presentation: Hong Kong
• [Presentation] RNAシークエンシングによる小児AMLの融合遺伝子探索.
  • Author(s): 三谷幸代, 坂本裕美, 柴 徳生, 林 泰秀, 吉田輝彦, 市川 仁.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 小児non-Down急性巨核芽球性白血病における遺伝子解析.
  • Author(s): 原 勇介, 柴 徳生, 大木健太郎, 朴 明子, 富澤大輔, 多賀 崇, 足立壮一, 荒川浩一, 多和昭雄, 堀部敬三, 林 泰秀.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] NUP98-NSD1 gene fusion is a strong poor prognostic factor in pediatric AML.
  • Author(s): Hara Y, Shiba N, Ichikawa H, Taki T, Shimada A, Kudo K, Tomizawa D, Taga T, Adachi S, Arakawa H, Tawa A, Hayashi Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Clonal architecture in a case of acute myeloid leukemia with trisomy 8 and MLL-AF9.
  • Author(s): Ohki K, Kama Y, Shiba N, Arai K, Park MJ, Sotomatsu M, Hayashi Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Genetic basisi of myeloid leukemogenesisi in Down syndrome.
  • Author(s): Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sanada M, Park MJ, Terui K, Kon A, Nagata Y, Sato-Otsubo A, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Gene expression profile in childhood BCP-ALL without common chimeric genes. The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Author(s): Iijima K, Kiyokawa N, Yoshihara H, Osumi T, Kato M, Kobayashi K, Okita H, Fujimoto J, Hanada R, Tsuchida M, Shimada H, Fukushima T, Koh K, Manabe A, Kikuchi A, Hayashi Y, Ohara A.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Genome-wide analysis of relapsed T cell acute lymphoblastic leukemia.
  • Author(s): Seki M, Hoshino N, Nishimura R, Okuno Y, Shiraishi Y, Yoshida K, Kato M, Kho K, Hanada R, Miyano S, Hayashi Y, Ogawa S, Takita J.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] 13q欠失を伴ったダウン症合併TAMとAMKLの遺伝子解析.
  • Author(s): 朴 明子, 吉田健一, 大木健太郎, 新井 心, 外松 学, 伊藤悦朗, 小川誠司, 林 泰秀.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Gata2 mutations are found in pediatric AML but not in other leukemias including JMML.
  • Author(s): Hara Y, Shiba N, Funato M, Oki K, Park MJ, Mizushima Y, Adachi S, Kobayashi M, Kinoshita A, Sotomatsu M, Arakawa H, Tawa A, Horibe K, Tsukimoto I, Hayashi Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Whole-exome resequencing reveals novel pathogenetic gene mutations in pediatric AML.
  • Author(s): Shiba N, Yoshida K, Okuno Y, Shiraishi Y, Nagata Y, Kon A, Chiba K, Tanaka H, Ohki K, Kato M, Terui K, Park MJ, Kanazawa T, Takita J, Kudo K, Arakawa H, Ito E, Sanada M, Miyano S, Ogawa S, Hayashi Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] Recurrent SETBP1 mutation in juvenile myelomonocytic leukemia and myelodysplastic syndrome.
  • Author(s): Shiba N, Hara Y, Park MJ, Ohki K, Fukushima K, Sako M, Kudo K, Arakawa H, Ito E, Hayashi Y.
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematolgy.
  • Place of Presentation: 札幌
• [Presentation] 全エクソーム解析による小児急性骨髄性白血病の新規原因遺伝子の同定.
  • Author(s): 柴 徳生, 林 泰秀.
  • Organizer: 第55回日本小児血液・がん学会学術集会（シンポジウム）
  • Place of Presentation: 福岡
• [Presentation] 小児白血病におけるSETBP1遺伝子変異の解析.
  • Author(s): 柴 徳生, 大木健太郎, 朴 明子, 工藤寿子, 福島啓太郎, 伊藤悦朗, 迫 正廣, 多和昭雄, 荒川浩一, 林 泰秀.
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 急性骨髄性白血病におけるWT1遺伝子変異の解析.
  • Author(s): 佐野弘純, 嶋田 明, 田渕 健, 滝 智彦, 村田知里, 朴 明子, 大木健太郎, 外松 学, 足立壮一, 多和昭雄, 小林良二, 堀部敬三, 土田昌宏, 花田良二, 月本一郎, 林 泰秀.
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 小児骨髄造血器腫瘍におけるCSF3R遺伝子異常の解析.
  • Author(s): 佐野仁志, 大木健太郎, 朴 明子, 柴 徳生, 原 勇介, 外松 学, 足立壮一, 堀部敬三, 多和昭雄, 花田良二, 月本一郎, 林 泰秀.
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡