Establishment of ALL cell line bank to identify genetic factors involving in drug-sensitivity for future precision medicine

• Project/Area Number: 15K09645
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Yamanashi
• Principal Investigator: INUKAI Takeshi 山梨大学, 大学院総合研究部, 准教授 (30293450)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Atsushi 山梨大学, 大学院総合研究部, 診療助教 (30610498) ; SHINOHARA Tamao 山梨大学, 大学院総合研究部, 医学研究員 (80747452)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 急性リンパ性白血病 / 化学療法 / 薬剤感受性 / 遺伝子変異 / 一塩基多型 / 白血病 / 遺伝子多型 / ゲノム編集 / 薬剤耐性

Outline of Final Research Achievements

To identify genetic factors that involve in the drug-sensitivity of childhood acute lymphoblastic leukemia (ALL), we established cell line bank. We collected 93 BCP-ALL and 24 T-ALL cell lines including 86 and 7 cell lines that were established from Japanese patients, respectively. In these cell lines, we performed genetic analyses including multiplex ligation-dependent probe amplification assay, gene mutation analyses using next-generation sequencer, SNP array analyses, and digital karyotyping by array CGH analyses. Using the cell line bank, we verified that glucocorticoid sensitivity was associated with gene expression levels of glucocorticoid receptor (Hematol Oncol 2018) and BIM (Leuk Res 2017). We also revealed that higher sensitivity to bortezomib was associated with IKZF1 gene deletion (PLoS One 2017). These observations suggested a usefulness of cell line bank for identification of genetic factors involving in the drug-sensitivity of ALL.

Research Products

• [Journal Article] Splicing variant profiles and single nucleotide polymorphisms of the glucocorticoid receptor gene in relation to glucocorticoid sensitivity of B-cell precursor acute lymphoblastic leukaemia. (2018)
  • Author(s): Huang M, Inukai T, Kagami K, Abe M, Shinohara T, Watanabe A, Somazu S, Oshiro H, Goi K, Goto H, Minegishi M, Iwamoto S, Urayama KY, Sugita K.
  • Journal Title: Hematol Oncol. Volume: 36(1) Issue: 1 Pages: 245-251
  • DOI: 10.1002/hon.2471
  • Peer Reviewed
• [Journal Article] Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese (2018)
  • Author(s): Urayama Kevin Y.、Takagi Masatoshi、Kawaguchi Takahisa、Matsuo Keitaro、Tanaka Yoichi、Ayukawa Yoko、Arakawa Yuki、Hasegawa Daisuke、Yuza Yuki、Kaneko Takashi、Noguchi Yasushi、Taneyama Yuichi、Ota Setsuo、Inukai Takeshi、Yanagimachi Masakatsu、Keino Dai、Koike Kazutoshi、Toyama Daisuke、Inazawa Johji 他16名
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 789-789
  • DOI: 10.1038/s41598-017-19127-7
  • Peer Reviewed / Open Access
• [Journal Article] Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression. (2017)
  • Author(s): Kasai S, Furuichi Y, Ando N, Kagami K, Abe M, Nakane T, Goi K, Inukai T, Saitoh S, Ohno S, Okazaki S, Nagano O, Saya H, Sugita K.
  • Journal Title: Cell Death and Disease Volume: 8 Issue: 6 Pages: e2857-e2857
  • DOI: 10.1038/cddis.2017.249
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lack of association between deletion polymorphism of BIM gene and in vitro drug sensitivity in B-cell precursor acute lymphoblastic leukemia (2017)
  • Author(s): Huang Meixian、Miyake Kunio、Kagami Keiko、Abe Masako、Shinohara Tamao、Watanabe Atsushi、Somazu Shinpei、Oshiro Hiroko、Goi Kumiko、Goto Hiroaki、Minegishi Masayoshi、Iwamoto Shotaro、Kiyokawa Nobutaka、Sugita Kanji、Inukai Takeshi
  • Journal Title: Leukemia Research Volume: 60 Pages: 24-30
  • DOI: 10.1016/j.leukres.2017.06.003
  • Peer Reviewed
• [Journal Article] TGFβ1 synergizes with FLT3 ligand to induce chemoresistant quiescence in acute lymphoblastic leukemia with MLL gene rearrangements. (2017)
  • Author(s): Tamai M, Furuichi Y, Kasai S, Ando N, Harama D, Goi K, Inukai T, Kagami K, Abe M, Ichikawa H, Sugita K.
  • Journal Title: Leuk Res. Volume: 61 Pages: 68-76
  • DOI: 10.1016/j.leukres.2017.08.013
  • Peer Reviewed
• [Journal Article] Anti-leukemic activity of bortezomib and carfilzomib on B-cell precursor ALL with IKZF1 deletion. (2017)
  • Author(s): Takahashi K, Inukai T, Imamura T, Yano M, , Nemoto A, Sato H, Huang M, Abe M, Kagami K, Shinohara T, Watanabe A, Somazu S, Oshiro H, Akahane K, Goi K, Kikuchi J, Furukawa Y, Goto H, Minegishi M, Iwamoto S, Sugita K.
  • Journal Title: PLoS One Volume: 12 Issue: 12 Pages: e0188680-e0188680
  • DOI: 10.1371/journal.pone.0188680
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells. (2017)
  • Author(s): Piao J, Takai S, Kamiya T, Inukai T, Sugita K, Ohyashiki K, Delia D, Masutani M, Mizutani S, Takagi M.
  • Journal Title: Cancer Lett Volume: 386 Pages: 131-140
  • DOI: 10.1016/j.canlet.2016.11.021
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcome of six-month maintenance chemotherapy for acute lymphoblastic leukemia in children. (2017)
  • Author(s): Kato M, Ishimaru S, Seki M, Yoshida K, Shiraishi Y, Chiba K, Kakiuchi N, Sato Y, Ueno H, Tanaka H, Inukai T, Tomizawa D, Hasegawa D, Osumi T, Arakawa Y, Aoki T, Okuya M, Kaizu K, Kato K, Taneyama Y, Goto H, Taki T, Takagi M, Sanada M, Koh K, Takita J, Miyano S, Ogawa S, Ohara A, Tsuchida M, Manabe A.
  • Journal Title: Leukemia. Volume: 31 Issue: 3 Pages: 580-584
  • DOI: 10.1038/leu.2016.274
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 急性リンパ性白血病の薬剤耐性機序 (2017)
  • Author(s): 犬飼岳史
  • Journal Title: 臨床血液 Volume: 57 Pages: 2011-2028
  • NAID: 130005250015
• [Journal Article] Erythrophagocytosis in T-cell type acute lymphoblastic leukaemia with near-tetraploidy. (2016)
  • Author(s): Watanabe A, Akahane K, Somazu S, Oshiro H, Goi K, Miyachi H, Kiyokawa N, Inukai T, Sugita K.
  • Journal Title: J Clin Pathol Volume: 69 Issue: 12 Pages: 1129-1132
  • DOI: 10.1136/jclinpath-2016-203915
  • Peer Reviewed
• [Journal Article] Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia. (2016)
  • Author(s): Sera Y, Yamasaki N, Oda H, Nagamachi A, Wolff L, Inukai T, Inaba T, Honda H.
  • Journal Title: Cancer Sci Volume: 107 Issue: 7 Pages: 890-898
  • DOI: 10.1111/cas.12945
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome-Positive Lymphoid Leukemia. (2016)
  • Author(s): Nemoto A, Saida S, Kato I, Kikuchi J, Furukawa Y, Maeda Y, Akahane K, Honna-Oshiro H, Goi K, Kagami K, Kimura S, Sato Y, Okabe S, Niwa A, Watanabe K, Nakahata T, Heike T, Sugita K, Inukai T.
  • Journal Title: Mol Cancer Ther. Volume: 15 Issue: 1 Pages: 94-105
  • DOI: 10.1158/1535-7163.mct-14-1065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia. (2015)
  • Author(s): Wu Z, Eguchi-Ishimae M, Yagi C, Iwabuki H, Gao W, Tauchi H, Inukai T, Sugita K, Ishii E, Eguchi M.
  • Journal Title: Br J Haematol. Volume: 171 Issue: 5 Pages: 818-829
  • DOI: 10.1111/bjh.13763
  • Peer Reviewed
• [Journal Article] Favorable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children's Cancer Study Group. (2015)
  • Author(s): Tomizawa D, Kato M, Takahashi H, Fujimura J, Inukai T, Fukushima T, Kiyokawa N, Koh K, Manabe A, Ohara A.
  • Journal Title: Int J Hematol. Volume: 102 Issue: 5 Pages: 602-610
  • DOI: 10.1007/s12185-015-1869-y
  • Peer Reviewed
• [Presentation] Association between asparaginase synthetase gene methylation status with karyotypes in childhood BCP-ALL (2017)
  • Author(s): Watanabe A, Inukai T
  • Organizer: 第59回日本小児血液がん学会
• [Presentation] B 前駆細胞型 ALL 細胞株の Ara-C 感受性における DCK遺伝子多型と変異の意義 (2017)
  • Author(s): 篠原珠緒, 犬飼岳史, 渡邊敦, 大城浩子, 赤羽弘資, 合井久美子, 黄媚賢, 阿部正子, 加賀美恵子, 後藤裕明, 峰岸正好, 岩本彰太郎, 杉田完爾
  • Organizer: 第59回日本小児血液がん学会
• [Presentation] BCP-ALL細胞株のthiopurine感受性におけるNT5C2遺伝子変異の意義 (2017)
  • Author(s): 杣津晋平, 犬飼岳史, 黄媚賢, 阿部正子, 加賀美恵子, 渡邊敦, 大城浩子, 赤羽弘資, 合井久美子, 杉田完爾
  • Organizer: 第79回日本血液学会
• [Presentation] 細胞質内μ鎖陽性のB前駆細胞性ALLに対するIdelalisibの抗白血病活性 (2017)
  • Author(s): 高橋和也, 犬飼岳史, 佐藤広樹, 廣瀬衣子, 渡邊敦, 杣津晋平, 合井久美子, 加賀美恵子, 阿部正子, 照井君典, 後藤裕明, 峰岸正好, 岩本彰太郎, 杉田完爾
  • Organizer: 第79回日本血液学会
• [Presentation] B前駆細胞型ALLのMTX感受性におけるTYMS遺伝子のtandem duplication多型の意義 (2016)
  • Author(s): 加藤 大貴, 犬飼 岳史, 三宅 邦夫, 加賀美 恵子, 阿部 正子, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 品川プリンスホテル（東京都品川区）
  • Year and Date: 2016-12-15
• [Presentation] BCP-ALL細胞株のABT737感受性におけるBcl2ファミリー遺伝子の意義 (2016)
  • Author(s): 黒田 格, 犬飼 岳史, 黄 媚賢, 加賀美 恵子, 阿部 正子, 中村 誠, 古市 嘉行, 佐藤 広樹, 高橋 和也, 根本 篤, 廣瀬 衣子, 小鹿 学, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 品川プリンスホテル（東京都品川区）
  • Year and Date: 2016-12-15
• [Presentation] B前駆細胞性ALLのAraC感受性におけるdeoxycytidine kinaseの意義 (2016)
  • Author(s): 黄 媚賢, 犬飼 岳史, 阿部 正子, 加賀美 恵子, 後藤 裕明, 峯岸 正好, 岩本 彰太郎, 杉原 英志, 渡邊 敦, 大城 浩子, 赤羽 弘資, 合井 久美子, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 品川プリンスホテル（東京都品川区）
  • Year and Date: 2016-12-15
• [Presentation] BCP-ALL細胞株のthiopurine感受性におけるNUDT15遺伝子多型の意義 (2016)
  • Author(s): 杣津 晋平, 犬飼 岳史, 森山 貴也, Yang Jun, 阿部 正子, 加賀美 恵子, 渡邊 敦, 大城 浩子, 赤羽 弘資, 合井 久美子, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 品川プリンスホテル（東京都品川区）
  • Year and Date: 2016-12-15
• [Presentation] B前駆細胞型ALL細胞株の薬剤感受性におけるCASP8遺伝子のins/del多型の意義 (2016)
  • Author(s): 篠原 珠緒, 犬飼 岳史, 渡邊 敦, 大城 浩子, 赤羽 弘資, 合井 久美子, 黄 媚賢, 阿部 正子, 加賀美 恵子, 後藤 裕明, 峰岸 正好, 岩本 彰太郎, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 品川プリンスホテル（東京都品川区）
  • Year and Date: 2016-12-15
• [Presentation] Association of germline polymorphisms in the ARID5B gene with its gene expression level and chemoresistance of BCP-ALL (2015)
  • Author(s): 玉井 望雅, 犬飼 岳史, 黄 媚賢, 篠原 珠緒, 渡邊 敦, 杣津 晋平, 大城 浩子, 古市 嘉行, 合井 久美子, 阿部 正子, 加賀美 恵子, 後藤 裕明, 峯岸 正好, 岩本 彰太郎, Kevin Urayama , 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
• [Presentation] Association of receptor isoform profiling and SNP typing of glucocorticoid(GC) with GC-sensitivity of BCP-ALL (2015)
  • Author(s): 黄 媚賢, 犬飼 岳史, 加賀美 恵子, 阿部 正子, 篠原 珠緒, 渡辺 敦, 杣津 晋平, 大城 浩子, 合井 久美子, 後藤 裕明, 峯岸 正好, 岩本 彰太郎, Kevin Urayama, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
• [Presentation] Association of rs924607 polymorphism located in CEP72 gene promoter with vincristine sensitivity of BCP-ALL in Japanese population (2015)
  • Author(s): 小鹿 学, 犬飼 岳史, 黄 媚賢, 加賀美 恵子, 阿部 正子, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
• [Presentation] Significance of 19-bp deletion polymorphism of DHFR gene in MTX-sensitivity of B-cell precursor ALL (2015)
  • Author(s): 加藤 大貴, 犬飼 岳史, 黄 媚賢, 加賀美 恵子, 阿部 正子, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
• [Presentation] Association of GSTM1 and GSTT1 deletion polymorphisms with MTX-sensitivity of BCP-ALL (2015)
  • Author(s): 篠原 珠緒, 犬飼 岳史, 渡邊 敦, 杣津 晋平, 大城 浩子, 合井 久美子, 黄 媚賢, 阿部 正子, 加賀美 恵子, 後藤 裕明, 峯岸 正好, 岩本 彰太郎, 阿部 洋, 杉田 完爾
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
• [Presentation] Molecular aspects of chemoresistance in poor prognostic ALL (2015)
  • Author(s): Takeshi Inukai
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 山梨県甲府市
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] 白血病細胞株を用いた小児ALLにおける抗がん剤感受性解析システムの確立 (2015)
  • Author(s): 犬飼 岳史, 黄 媚賢, 渡邊 敦, 杣津 晋平, 篠原 珠緒, 合井 久美子, 加賀美 恵子, 阿部 正子, 後藤 裕明, 杉田 完爾
  • Organizer: 日本小児科学会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2015-04-17
• [Book] 免疫症候群II（急性リンパ性白血病） (2016)
  • Author(s): 犬飼 岳史
  • Total Pages: 859
  • Publisher: 日本臨床社
• [Book] 小児血液・腫瘍学 (がんの細胞生物学） (2015)
  • Author(s): 犬飼 岳史
  • Total Pages: 585
  • Publisher: 診断と治療社