Development of new diagnostic method for refractory maliganant diseases

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17H04110
• Research Institution: Kyoto University
• Principal Investigator: 足立 壯一 京都大学, 医学研究科, 教授 (10273450)
• Co-Investigator(Kenkyū-buntansha): 上久保 靖彦 京都大学, 医学研究科, 特定教授 (60548527)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: ゲノム / フローサイトメトリー法 / レーザーマイクロダイセクション / 癌遺伝子 / 予後因子

Outline of Annual Research Achievements

『難治性造血器悪性腫瘍・固形腫瘍における新規共通増殖機構の解明とそれをターゲットとした新規検査法の開発』を深化・実用化するために(1)～(2)を通じた研究・開発を行う。(1)難治性腫瘍の新規予後因子の探索とそれを利用した新規検査法の開発　A:急性骨髄性白血病の新規予後因子探索；AML-05登録患者検体を用いて、網羅的遺伝子解析を遂行中し、MLL転座型AMLにおいて、新規遺伝子変異を見出し、変異遺伝子の機能解析を遂行する。AML細胞株を用いて、in vitro及びin vivoにおける細胞死誘導機序を解析し、CDK4/6阻害剤によるin vitro及びin vivoにおける抗腫瘍効果を検討した。
B: 難治性腫瘍予後不良因子をターゲットとした新規遺伝子スイッチ法の開発
CML細胞株MLL-AML細胞株を用い、PI-Pライブラリー（SAHA、Chb-conjugated）スクリーニングを施行し、IC50が1μM以下のHITsを取得し、現在そのValidationを施行中である。野生型マウスを使用したHITsの簡易毒性をラボにて施行したところ、毒性が大きいものと、毒性が比較的小さいものを同定した。(2)新規検査技術の開発　A：Xeno-Graft Banking新規マウス生体内ヒト腫瘍細胞増幅技術；JCCG 再発ALL観察研究登録中の患者検体をNOGマウスを用いて増幅、保存中である。　B:フローサイトメーターによる白血病微小残存病変の検出；JCCG AML臨床試験（AML-D11）の患者検体を用いて、三重大学とともに、微小残存病変を解析し、MRD陽性例は予後不良であることを見出し、昨年のアメリカ血液学会で発表した。C:レーザーマイクロダイセクション法の開発；JCCG再発AML観察研究登録患者の再発時検体のG-CSFR typeIV発現量解析を中央診断施設として解析中である。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing. (2020)
  • Author(s): Terui K, Toki T, Taga T, Iwamoto S, Miyamura T, Hasegawa D, Moritake H, Hama A, Nakashima K, Kanezaki R, Kudo K, Saito AM, Horibe K, Adachi S, Tomizawa D, and Ito E
  • Journal Title: Genes Chromosomes Cancer Volume: 59 Pages: 160-167
  • DOI: 10.1002/gcc.22816.
  • Peer Reviewed
• [Journal Article] Predisposition to prolonged neutropenia after chemotherapy for paediatric acute myeloid leukaemia is associated with better prognosis in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. (2020)
  • Author(s): Aoki T, Takahashi H, Tanaka S, Shiba N, Hasegawa D, Iwamoto S, Terui K, Moritake H, Nakayama H, Shimada A, Koh K, Goto H, Kosaka Y, Saito A, Horibe K, Kinoshita A, Tawa A, Taga T, Adachi S, Tomizawa D.
  • Journal Title: Brit J Haematol Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed
• [Journal Article] Continuous deep sedation at the end of life in children with cancer: experience at a single center in Japan. (2020)
  • Author(s): Maeda S, Kato I, Umeda K, Hiramatsu H, Takita J, Adachi S, Tsuneto S.
  • Journal Title: Pediatr Hemato Oncol Volume: 印刷中 Pages: 印刷中
  • Peer Reviewed
• [Journal Article] Retrospective analysis of children with high-risk acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation following complete remission with initial induction chemotherapy in the AML-05 clinical trial. (2019)
  • Author(s): Hyakuna N, Hashii Y, Ishida H, Umeda K, Takahashi Y, Nagasawa M, Yabe H, Nakazawa Y, Koh K, Goto H, Fujisaki H, Matsumoto K, Kakuda H, Yano M, Tawa A, Tomizawa D, Taga T, Adachi S, and Kato K.
  • Journal Title: Pediatr Blood Cancer Volume: 66 Pages: e27875.
  • DOI: 10.1002/pbc.27875.
  • Peer Reviewed
• [Journal Article] Transcriptome Analysis Offers a Comprehensive Illustration of the Genetic Background of Pediatric Acute Myeloid Leukemia. (2019)
  • Author(s): Shiba N, Hara Y, Shiraishi Y, Matsuo H, Chiba K, Kaburagi T, Ohki K, Sanada M, Okubo J, Tomizawa D, Taki T, Sotomatsu M, Horibe K, Adachi S, Tawa A, Miyano S, Ogawa S, Hayashi Y.
  • Journal Title: Blood Adv Volume: 3 Pages: 3157-3169
  • DOI: 10.1182/bloodadvances.2019000404.
  • Peer Reviewed / Open Access
• [Journal Article] Supportive care for hemostatic complications associated with pediatric leukemia: a national survey in Japan. (2019)
  • Author(s): Osone S, Fukushima K, Yano M, Kakazu M, Sano H, Kato Y, Shinkoda Y, Shinoda K, Mori N, Adachi S.
  • Journal Title: Int J Hematol Volume: 110 Pages: 743-750
  • DOI: 10.1007/s12185-019-02740-9.
  • Peer Reviewed
• [Journal Article] Characteristics and outcomes of children with acute myeloid leukemia and Down syndrome who are ineligible for clinical trials due to severe comorbidities. (2019)
  • Author(s): Nakashima K, Hasegawa D, Tomizawa D, Miyamura T, Hama A, Iwamoto S, Terui K, Adachi S, Taga T.
  • Journal Title: Pediatr Blood Cancer Volume: 66 Pages: e27942
  • DOI: 10.1002/pbc.27942
  • Peer Reviewed
• [Presentation] Post-induction minimal residual disease measured by flow cytometry and deep sequencing of mutant GATA1 are both significant prognostic factors for children with myeloid leukemia and Down syndrome: a nationwide prospective study of the Japanese Pediatric Leukemia/Lymphoma Study Group. (2019)
  • Author(s): Taga T, Tanaka S, Terui K, Iwamoto S, Hiramatsu H, Miyamura T, Hashii Y, Hasegawa D, Moritake H, Nakayama H, Takahashi H, Shimada A, Taki T, Toki T, Ito E, Koh K, Hasegawa D, Hama A, Saito AM, Adachi S, Tomizawa D.
  • Organizer: 61st Annual Meeting of the American Society of Hematology,
  • Int'l Joint Research
• [Presentation] Clinical Features of Children with Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis in Japan: Retrospective Nationwide Survey. (2019)
  • Author(s): Ishida H, Sarashina T, Matsumura R, Umeda K, Mitsui T, Fujita N, Tomizawa D, Urayama K, Ishida Y, Taga T, Takagi M, Adachi S, Manabe A, Imamura T, Koh K, Shimada A.
  • Organizer: 61st Annual Meeting of the American Society of Hematology,
  • Int'l Joint Research
• [Presentation] Coexistence and prognostic significance of EVI1 expression and driver mutations in KMT2A-rearranged acute myeloid leukemia. (2019)
  • Author(s): Matsuo H, Yoshida K, Nakatani K, Kamikubo Y, Tomizawa D, Taga T, Kiyokawa N, Ogawa S, Meggendorfer M, Haferlach C, Adachi S.
  • Organizer: 61st Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Significant features of DNA methylation at bivalent promotor and repressed polycomb regions in pediatric AML-the JCCG study, JPLSG AML05 (2019)
  • Author(s): Yamato G, Kawai T, Shiba N, Hara Y, Ohki K, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
  • Organizer: 61st Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Clinical Features of Pediatric Acute Myeloid Leukemia with TP53 and CDKN2A/2B Copy Number Alterations. (2019)
  • Author(s): Hara Y, Taki T, Yamato G, Yoshida K, Shiozawa Y, Shiba N, Kaburagi T, Shiraishi Y, Ohki K, Kawamura M, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Toki T, Kiyokawa N, Tomizawa D, Taga T, Ito E, Horibe K, Miyano S, Ogawa S, Adachi S, Hayashi Y.
  • Organizer: 61st Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Recurrent gene mutations in pediatric AML patients by targeted sequencing ―the JCCG study, JPLSG AML-05― (2019)
  • Author(s): Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, Shiraishi Y, Ohki K, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Taga T, Adachi S, Ogawa S, Hayashi Y.
  • Organizer: 61st Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] The detection of minor clones with somatic KIT D816V mutations by droplet digital PCR in pediatric de novo AML. (2019)
  • Author(s): Sasaki K, Uchiyama Y, Ikeda J, Yoshitomi M, Shimosato-Wada Y, Tokumasu M, Matsuo H, Yoshida K, Ohki K, Yamato G, Hara Y, Kinoshita A, Tomizawa D, Taga T, Adachi S, Tawa A, Horibe K, Matsumoto N, Ito S, Hayashi Y, Shiba N.
  • Organizer: 61st Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Remarks] 血液生体防御学研究室
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/human_health/mt0302/