演題詳細

一般口演 / Oral Session

一般口演 25 (Oral Session 25) :CML:基礎 2

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日程
2013年10月11日(金)
時間
14:25 - 15:25
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
中前 博久 (Hirohisa Nakamae):1
1:大阪市立大学大学院医学研究科 血液腫瘍制御学
 
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Ponatinib induced thrombocytopenia might be due to the inhibition of proplatelet formation

演題番号 : OS-1-128

村井 一範 (Kazunori Murai):1、古和田 周吾 (Shugo Kowata):1、菅原 教史 (Norifumi Sugawara):1、藤澤 佑香 (Yuka Fujisawa):1、佐々木 了政 (Ryousei Sasaki):1、藤島 行輝 (Yukiteru Fujishima):1、峯 貴浩 (Takahiro Mine):1、小宅 達郎 (Tatsuo Oyake):1、伊藤 薫樹 (Shigeki Ito):1、石田 陽治 (Yoji Ishida):1

1:Hematology/Oncology, Iwate Medical Univ., Japan

 

Ponatinib is identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML (Chronic Myeloid Leukemia). Ponatinib has substantial activity in heavily pretreated patients and those with refractory T315I mutation. However, approximately one third of ponatinib-treated patients had moderate to severe thrombocytopenia. The mechanism of ponatinib-induced thrombocytopenia remains unknown. We studied in vitro culture of megakaryocytic colonies (CFU-Meg), megakaryocyte ploidy analyses in vitro culture and proplatelet formation (PPF) assay in vitro. CFU-Meg colony formation did not decrease significantly at 0.001, 0.01, 0.1, 1, 10 and 100 nM of ponatinib. PPF decreased significantly at 0.1, 1, 10, 100 nM ponatinib.The decreases in PPF were cancelled significantly by the addition of Y27632, Rho-associate kinase ROCK inhibitor. There was no difference in DNA ploidy of cultured megakaryocytes in the presence of ponatinib. Activated Rho was upregulated and that activated Rac was downregulated at 50 nM of ponatinib in murine platelets. Ponatinib reduced levels of phosphorylated Lyn (p-Lyn) in murine platelets. The Rho/ ROCK pathway was reported to be negative regulators and positive regulators in PPF. Ponatinib induced thrombocytopenia might not be due to the inhibition of megakaryocyte colony formations but the inhibition of PPF of megakaryocytes via pathways including Rho/Rock and Rac.

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