演題詳細

一般口演 / Oral Session

【E】一般口演 9 (Oral Session 9) :CML:Basic Research 1

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日程
2013年10月11日(金)
時間
09:30 - 10:30
会場
第7会場 / Room No.7 (ロイトン札幌 2F リージェント)
座長・司会
木村 晋也 (Shinya Kimura):1
1:Blood and Lung and Tumor Institute, Saga University, Japan
 
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Targeting the hedgehog signaling pathway limits the self-renewal of BCR-ABL1 positive leukemia cells

演題番号 : OS-1-41

田内 哲三 (Tetsuzo Tauchi):1、片桐 誠一朗 (Seiichiro Katagiri):1、岡部 聖一 (Seiichi Okabe):1、南 陽介 (Yosuke Minami):2、直江 知樹 (Tomoki Naoe):3、大屋敷 一馬 (Kazuma Ohyashiki):1

1:1st Dept. Int. Med., Tokyo Medical Univ., Japan、2:Dept. Hematol. Oncol., Kobe Univ., Japan、3:Dept. of Hematol. Oncol., Nagoya Univ., Japan

 

In the present study, we investigated the molecular mechanisms by which vismodegib and LDE225 regulate the self-renewal of BCR-ABL1 positive leukemia cells. We serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n=1; T315I BCR-ABL1) or Ph-positive acute lymphoblastic leukemia (n=2, T315I BCR-ABL1) into NOG mice. NOD/SCID mice were injected with BCR-ABL1 positive cells from NOG mice then treated with Hedgehog inhibitors for 28 days. All mice demonstrated the engraftment of leukemia. However, the treatment with vismodegib or LDE225 reduced the population of CD34+CD38- positive cells. We isolated human CD45+ cells from mice and injected equivalent numbers of leukemia cells into secondary recipients. Following 30 days, all mice received BCR-ABL1 cells from vehicle treated mice engrafted with leukemia. In contrast, leukemia engraftment was not detected in recipient mice (n=6) from vismodegib or LDE225 treated donors. These results demonstrate the persistent effects of hedgehog inhibition on long term self-renewing BCR-ABL1-positive leukemia cells. Next we investigate the mechanisms that limit the self-renewal of BCR-ABL1-positive cells by Hedgehog inhibitors. Both vismodegib and LDE225 induced the expressions of p21Cip1, pATM, pChk2 and γH2AX, and reduced the expression of Gli-1, Gli-2, Bcl-2, and cyclin D2. Our preclinical results indicate that vismodegib and LDE225 have potential as an important option for controlling the drug-resistant leukemia initiating cells in BCR-ABL1 positive leukemia.

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