健康骨髓中包含有許多種細胞類型,，其中就有負責(zé)產(chǎn)生血小板的巨核細胞,。Bcl-xL蛋白對于巨核細胞的存活非常重要,，在腫瘤患者化療化后,，由于促凋亡蛋白Bax和Bak被活化,，骨髓中多種細胞種類會被殺死包括巨核細胞,。因化療對血小板和巨核細胞的毒性緣故,，患者體內(nèi)血小板數(shù)量減少。
近日,，來自澳洲墨爾本沃爾特與伊麗莎醫(yī)學(xué)研究所的科學(xué)家們在The Journal of Experimental Medicine雜志上發(fā)表文章稱,，他們新發(fā)現(xiàn)了化療引發(fā)癌癥患者體內(nèi)血小板數(shù)量減少的一種新機制。
細胞生死命運是由Bcl-2家族蛋白所決定的,。一些Bcl-2家族凋亡蛋白質(zhì)會促進細胞死亡,，而一些蛋白質(zhì)則促使細胞存活。在過去十年里,，我們認(rèn)為是巨核細胞發(fā)生類似細胞死亡的過程后才形成血小板,，但Josefsson博士等研究人員檢測細胞程序性死亡所需的關(guān)鍵分子后推翻了這一假設(shè)，血小板并不是由巨核細胞發(fā)生類似細胞死亡后形成的,。
研究發(fā)現(xiàn)在巨核細胞形成血小板這一過程中,，Bcl-2家族中促凋亡蛋白并非關(guān)鍵蛋白。Josefsson博士說：化療通過激活Bcl-2家族蛋白質(zhì)來殺死巨核細胞,，那么癌癥患者在化療間期就不能制造出足夠地血小板,。
過去10年中，科學(xué)家們一直想要弄明白Bcl-2蛋白在血小板形成中的作用,。而這項研究很好地解決了有關(guān)血小板如何形成的爭論,，同時也有助于開發(fā)出新的策略來有效防止化療帶來的血小板減少癥。（生物谷Bioon.com）
doi:10.1084/jem.20110750
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Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
Emma C. Josefsson1,2,7, Chloé James1, Katya J. Henley1,2, Marlyse A. Debrincat1,2,7, Kelly L. Rogers5,7, Mark R. Dowling6,7,et al.
It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-xL resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak-/- Bax-/- hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.
