健康骨髓中包含有许多种细胞类型，其中就有负责产生血小板的巨核细胞。Bcl-xL蛋白对于巨核细胞的存活非常重要，在肿瘤患者化疗化后，由于促凋亡蛋白Bax和Bak被活化，骨髓中多种细胞种类会被杀死包括巨核细胞。因化疗对血小板和巨核细胞的毒性缘故，患者体内血小板数量减少。
近日，来自澳洲墨尔本沃尔特与伊丽莎医学研究所的科学家们在The Journal of Experimental Medicine杂志上发表文章称，他们新发现了化疗引发癌症患者体内血小板数量减少的一种新机制。
细胞生死命运是由Bcl-2家族蛋白所决定的。一些Bcl-2家族凋亡蛋白质会促进细胞死亡，而一些蛋白质则促使细胞存活。在过去十年里，我们认为是巨核细胞发生类似细胞死亡的过程后才形成血小板，但Josefsson博士等研究人员检测细胞程序性死亡所需的关键分子后推翻了这一假设，血小板并不是由巨核细胞发生类似细胞死亡后形成的。
研究发现在巨核细胞形成血小板这一过程中，Bcl-2家族中促凋亡蛋白并非关键蛋白。Josefsson博士说：化疗通过激活Bcl-2家族蛋白质来杀死巨核细胞，那么癌症患者在化疗间期就不能制造出足够地血小板。
过去10年中，科学家们一直想要弄明白Bcl-2蛋白在血小板形成中的作用。而这项研究很好地解决了有关血小板如何形成的争论，同时也有助于开发出新的策略来有效防止化疗带来的血小板减少症。（生物谷Bioon.com）
doi:10.1084/jem.20110750
PMC:
PMID:
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.
