日本語フィールド
著者：*Tatsuya Masuda, Shintaro Maeda, Sae Shimada, Naoya Sakuramoto, Ken Morita, Asami Koyama, Kensho Suzuki, Yoshihide Mitsuda, Hidemasa Matsuo, Hirohito Kubota, Itaru Kato, Kuniaki Tanaka, Junko Takita, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Souichi Adachi, Hideyo Hirai, Shuichi Mizuta, Kazuhito Naka, Yoichi Imai, Shinya Kimura, Hiroshi Sugiyama, Yasuhiko Kamikubo題名：RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia 発表情報：Cancer Sci 巻: 113 号: 2 ページ: 529-539キーワード：Fusion Proteins; Gene Expression Regulation; Leukemia; Lymphoid; Philadelphia Chromosome; RUNX1 protein; bcr-abl; human概要：The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph+ ALL. However, a portion of them still become refractory to the therapy mainly through acquiring mutations in BCR-ABL1 gene, necessitating a novel strategy to treat TKI-resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently down-regulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph+ ALL cell line. In a good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph+ ALL PDX cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph+ ALL.抄録：英語フィールド
Author：*Tatsuya Masuda, Shintaro Maeda, Sae Shimada, Naoya Sakuramoto, Ken Morita, Asami Koyama, Kensho Suzuki, Yoshihide Mitsuda, Hidemasa Matsuo, Hirohito Kubota, Itaru Kato, Kuniaki Tanaka, Junko Takita, Masahiro Hirata, Tatsuki R Kataoka, Tatsutoshi Nakahata, Souichi Adachi, Hideyo Hirai, Shuichi Mizuta, Kazuhito Naka, Yoichi Imai, Shinya Kimura, Hiroshi Sugiyama, Yasuhiko KamikuboTitle：RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia Announcement information:Cancer Sci Vol: 113 Issue: 2 Page: 529-539Keyword：Fusion Proteins; Gene Expression Regulation; Leukemia; Lymphoid; Philadelphia Chromosome; RUNX1 protein; bcr-abl; humanAn abstract：The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph+ ALL. However, a portion of them still become refractory to the therapy mainly through acquiring mutations in BCR-ABL1 gene, necessitating a novel strategy to treat TKI-resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently down-regulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph+ ALL cell line. In a good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph+ ALL PDX cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph+ ALL.