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Blood, 2 July 2009, Vol. 114, No. 1, pp. 4.
Megakaryocytes survive without survivinBOSTON UNIVERSITY Abstract Survivin has been described as an important regulator of late mitosis and as antiapoptotic in various cells. In this issue of Blood, Wen and colleagues describe a megakaryocyte-specific knockout of survivin, with no influence on megakaryocyte survival, and a stimulating effect on polyploidy.1 Megakaryocytes are one of the few cell types that undergo a modified form of the cell cycle termed endomitosis.2 In the course of endomitosis, megakaryocytes progress into mitosis, but exit the cell cycle prior to cytokinesis. The extent to which the mitotic machinery, such as the chromosome passenger complex (CPC) and the cleavage furrow, contributes to endomitosis remains controversial. Recent studies suggest that endomitosis results from a late failure of mitosis, including the lack of RhoA activation and reduced accumulation of nonmuscle myosin IIA in the contractile ring.3,4 Other studies indicate that earlier events are also defective during endomitosis. These include the observation that neither survivin nor aurora B, 2 essential components of the CPC, is properly localized in most large, late-anaphase murine megakaryocytes.5 Moreover, both survivin mRNA and protein are significantly down-regulated in megakaryocytes as compared with differentiating erythroid cells.6 In contrast to these findings, other groups were able to detect survivin protein in human polyploid megakaryocytes.4 In this issue of Blood, Wen et al take advantage of the PF4-Cre transgenic strain to specifically delete survivin from megakaryocytes. In their thorough analyses, they first reveal important issues to consider in the application of this mouse binary system in vivo. Namely, Cre-directed excision of survivin in megakaryocytes was much lower in vivo, with nearly 70% excision noted in vitro (upon transduction of Cre into floxed cells), as compared with the less than 10% excision seen in the CD41-positive population from bone marrow of the binary mouse system. The authors discover that survivin is required for survival of megakaryocyte progenitors in vivo. This result is consistent with the known requirement for survivin in proliferating hematopoietic cells. However, they also found that deletion of survivin by the PF4-Cre strain or by retroviral expression of Cre had no effect on survival, and it actually leads to increased polyploidization of megakaryocytes. Thus, it appears that this component of the CPC is not required for megakaryocyte polyploidization, indicating that the difference between an endomitotic and proliferative cell cycle is evident early in mitosis. What explains the difference between expression of survivin in murine and human megakaryocytes? It is possible that human megakaryocytes tend to reach significantly lower ploidy states than murine counterparts. Second, the source of the survivin antibody and the method of its application during immunostaining of large megakaryocytes could impact the sensitivity of detection. Whether survivin is normally localized in some megakaryocytes or not, the current study shows that it is dispensable for polyploidization in this lineage. In view of the current and earlier studies, an interesting possibility to consider would be that interference with actin polymerization and stabilization (as expected with aberrant Rho signaling4) could impact proper midzone formation, which, in turn, might affect proper localization (and consequent stability) of APC components. It is also possible, and perhaps more likely, that polyploidy in megakaryocytes is a result of several independent but well-programmed mitotic hits.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
