難治性血液腫瘍疾患に対する新規治療法の開発と新規細胞死機序の探索

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23390273
• Research Institution: Kyoto University
• Principal Investigator: 足立 壯一 京都大学, 医学(系)研究科(研究院), 教授 (10273450)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 難治性血液腫瘍 / 細胞死 / 遺伝子変異 / 遺伝子発現 / 微小残存病変 / 新規予後因子

Research Abstract

難治性血液腫瘍疾患の新規治療法の開発を目指し、（１）難治性白血病及び難治性固形腫瘍のin vivoにおける細胞死機序の検索（２）難治性白血病の新規予後因子の検索（３）急性骨髄性白血病(AML)の微少残存病変(MRD)分画における白血病幹細胞の同定と機能の検討、を行った。（１）アメリカFDAに承認され、難治性Ph陽性白血病に対する臨床試験が開始されている新薬ponatinibをin vitroにおいて、T315I変異（現在のチロシンキナーゼ阻害剤すべてに耐性の変異）Ph陽性白血病細胞株を投与した。細胞死機序はアポトーシスでアポトーシスを阻害するとオートファジーが観察された。 (2)AML-05プロトコール余剰検体を用いて、KIT変異を解析した。 t(8;21)107例中45例(42％)、inv16 31例中12例(39％)に同定され、変異陽性例は変異陰性例と比較して、無病生存率の低下（P=0.031）、再発率の上昇(p=0.019)が見られたが、全生存率には有意差はなかった(P=0.901)。(3) ダウン症候群（DS）に合併したAML (AML-DS)患者では、治療終了後に、2カラー法のフローサイトメトリーでの微小残存病変（MRD）陽性４例とも長期生存していることから、DS患者の骨髄回復期の抗原発現は非ダウン症（NDS）患者とは異なっている可能性が考えられた。DS児およびNDS児の骨髄、末梢血を用いたFCM測定により、DS児のCD34+CD33+骨髄前駆細胞にはCD56(NCAM)が発現していることが示された。一方、NDS児においてはほとんど認められなかった。CD56はDS児においては、CD34+CD33+CD56+骨髄前駆細胞の存在を考慮した上で評価に用いる必要があり、本成果は、DS-AMLにおける正確なFCM-MRD評価の一助となることが期待される。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

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: Brit J Haematol Volume: 印刷中 Pages: 印刷中
  • DOI: doi: 10.1111/bjh.12559.
  • Peer Reviewed
• [Journal Article] Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. (2014)
  • Author(s): Muramatsu H, Sakaguchi H, Taga T, Tabuchi K, Adachi S, Inoue M, Kitoh T, Suminoe A, Yabe H, Azuma E, Shioda Y, Ogawa A, Kinoshita A, Kigasawa H, Osugi Y, Koike K, Kawa K, Kato K, Atsuta Y, Kudo K.
  • Journal Title: Pediatr Blood Cancer Volume: 61 Pages: 925-927
  • DOI: 10.1002/pbc.24883.
  • Peer Reviewed
• [Journal Article] Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children. (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Moriya-Saito A, Kudo K, Taga T, Iwamoto S, Shimada A, , Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Kigasawa H, Kosaka Y, Miyachi H, Horibe K, Nakahata T, and Adachi S.
  • Journal Title: Leukemia Volume: 27 Pages: 2413-2416
  • DOI: 10.1038/leu.2013.153.
  • 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, and 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, and Ito E.
  • Journal Title: Blood Volume: 121 Pages: 3181-3184
  • DOI: 10.1182/blood-2012-01-405746.
  • 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
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders (2013)
  • Author(s): Yoshida K, Toki T, Sanada M, Park M, 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, Miyano S, Kojima S, Ito E, Ogawa S.
  • Journal Title: Nature Genet Volume: 45 Pages: 1293-1299
  • DOI: 10.1038/ng.2759.
  • Peer Reviewed
• [Journal Article] Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. (2013)
  • Author(s): Tomizawa D, Tawa A, Watanabe T, Saito AM, Kudo K, Taga T, Iwamoto S, Shimada A, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Kiyokawa N, Isoyama K, Mizutani S, Hara J, Horibe K, Nakahata T, Adachi S.
  • Journal Title: Int J Hematol Volume: 98 Pages: 578-588
  • DOI: 10.1007/s12185-013-1492-2
  • Peer Reviewed
• [Presentation] Poor prognosis with different induction rate was observed in children with acute myeloid leukemia and FLT3-ITD according to the ITD/WT allelic ratio: A result from the Japanese Pediatric Leukemia/Lymphoma Study Group. (2013)
  • Author(s): Shimada A, Yamashita Y, Tomizawa D, Tawa A, Watanabe T, Yokozawa T, Kudo K, Taga T, Iwamoto S, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Goto H, Kosaka Y, Moriya-Saito A, Fujimoto J, Horibe K, Oki K, Hayashi Y, and Adachi S
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • 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 M, Tomizawa D, Taga T, Moriya-Saito A, Fujimoto J, Arakawa H, Tawa A, Horibe K, Adachi S, and Hayashi Y
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131207-20131210
• [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, Yoshida K, Nagata Y, Kon A, Okuno Y, Shiraishi Y, Kato M, Park M, Ohki K, Takita J, Kanazawa T, Kudo K, Ito E, Sanada M, Tomizawa D, Tawa A, Adachi S, Miyano S, Ogawa S, and Hayashi Y.
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131207-20131210
• [Presentation] CSF3Rgene mutations in myeloid malignancy of childhood. (2013)
  • Author(s): Sano H, Ohki K, Park M, Hara Y, Shiba N, Tomizawa D, Taga T, Moriya-Saito A, Fujimoto J, Tawa A, Horibe K, Adachi S, and Hayashi Y.
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131207-20131210
• [Presentation] Low frequency and ooor 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 M, Sano H, Hara Y, Shiba N, Tomizawa D, Taga T, Moriya-Saito A, Fujimoto J, Tawa A, Horibe K, Adachi S, and Hayashi Y.
  • Organizer: American Society of Hematology 55th Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Year and Date: 20131207-20131210
• [Presentation] Inhibitor of apoptosis proteins family genes expression in childhood (2013)
  • Author(s): Hidemitsu Kurosawa, Yuya Sato, Mayuko Okuya, Keitaro Fukushima, Osamu Arisaka, Myoung-ja Park, Hirotaka Matsui, Toshiya Inaba, Takeshi Inukai, Junichiro Fujimoto, Akio Tawa, Daisuke Tomizawa, Takashi Taga, Souichi Adachi, Keizo Horibe, Yasuhide Hayashi
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 20131129-20131201
• [Presentation] A diversity of cases in AML with promyelocytic differentiation ; A report from JPLSG (2013)
  • Author(s): Hiroyuki Takahashi, Hiromichi Matsushita, Akitoshi Kinoshita, Tomohiko Taki, Takao Deguchi, Nobutaka Kiyokawa, Yoshiko Hashii, Yasuhide Hayashi, Daisuke Tomizawa, Takashi Taga, Akiko Tawa, Souichi Adachi, Miharu Yabe, Hayato Miyachi
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20131011-20131013
• [Presentation] Investigation of the clinical significance of CEBPA mutation in child AML : The JPLSG AML-05 study (2013)
  • Author(s): Matsuo H, Itoh H, Adachi S, et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20131011-13
• [Presentation] Prognostic impact of KIT mutation in t(8;21) childhood AML : The JPLSG AML-05 trial (2013)
  • Author(s): Tokumasu M, Itoh H, Adachi S, et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20131011-13
• [Presentation] Four AML patients with Down syndrome who remain minimal residual disease positive without relapse (2013)
  • Author(s): Hiramatsu H, Watanabe K, Adachi S, et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20131011-13
• [Presentation] Chemotherapy prior to HSCT is beneficial for pediatric RAEB/RAEB-T (2013)
  • Author(s): Shimada A, Adachi S, et al
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 20131011-13
• [Presentation] 小児急性骨髄性白血病の治療成績：JPLSG AML-05臨床試験より Outcome of acute myeloid leukemia in children : a report from the JPLSG AML-05 (2013)
  • Author(s): 富澤大輔、多和昭雄、渡辺智之、齋藤明子、康 勝好、気賀沢寿人、小阪嘉之、堀部敬三、中畑龍俊、足立壮一
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島市
  • Year and Date: 20130419-20130421
• [Presentation] 小児急性骨髄性白血病寛解導入療法において支持療法が有害事象に与える影響 Significance of Supportive Care During Induction Chemotherapy for Childhood AML (2013)
  • Author(s): 長谷川大一郎、工藤寿子、多和昭雄、照井君典、岩本彰太郎、木下明俊、高橋浩之、中山秀樹、齋藤明子、足立壮一
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島市
  • Year and Date: 20130419-20130421
• [Book] チーム医療のための血液がんの標準的化学療法 (2013)
  • Author(s): 足立壮一/直江知樹、堀部敬三監修
  • Total Pages: 279-293/461
  • Publisher: メディカル・サイエンス・インターナショナル社
• [Book] ここまできた白血病/MDS治療 (2013)
  • Author(s): 足立壮一/金倉譲、松村到編集
  • Total Pages: 233-241/340
  • Publisher: 中山書店
• [Remarks] 京都大学医学研究科人間健康科学系専攻検査応用開発学血液・生体防御研究室
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/human_health/mt0302
• [Remarks] 京都大学医学研究科人間健康科学系専攻検査応用開発学血液・生体防御学研究室
  • URL: http://adachilab.web.fc2.com/index.html