The Journal of Experimental Medicine
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Published online June 18, 2007
doi:10.1084/jem.20062395
The Journal of Experimental Medicine, Vol. 204, No. 7, 1603-1611
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Leung et al.
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ARTICLE

 Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells

Cindy G. Leung1,2,4, Yanfei Xu1,2, Bretton Mularski1,2, Hui Liu1,2, Sandeep Gurbuxani3, and John D. Crispino1,2,4

1 Committee on Cancer Biology, 2 Ben May Institute for Cancer Research, and 3 Department of Pathology, The University of Chicago, Chicago, IL 60637
4 Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611

CORRESPONDENCE John Crispino: j-crispino{at}northwestern.edu

Survivin, which is the smallest member of the inhibitor of apoptosis protein (IAP) family, is a chromosomal passenger protein that mediates the spindle assembly checkpoint and cytokinesis, and also functions as an inhibitor of apoptosis. Frequently overexpressed in human cancers and not expressed in most adult tissues, survivin has been proposed as an attractive target for anticancer therapies and, in some cases, has even been touted as a cancer-specific gene. Survivin is, however, expressed in proliferating adult cells, including human hematopoietic stem cells, T-lymphocytes, and erythroid cells throughout their maturation. Therefore, it is unclear how survivin-targeted anticancer therapies would impact steady-state blood development. To address this question, we used a conditional gene-targeting strategy and abolished survivin expression from the hematopoietic compartment of mice. We show that inducible deletion of survivin leads to ablation of the bone marrow, with widespread loss of hematopoietic progenitors and rapid mortality. Surprisingly, heterozygous deletion of survivin causes defects in erythropoiesis in a subset of the animals, with a dramatic reduction in enucleated erythrocytes and the presence of immature megaloblastic erythroblasts. Our studies demonstrate that survivin is essential for steady-state hematopoiesis and survival of the adult, and further, that a high level of survivin expression is critical for proper erythroid differentiation.

Abbreviations used: CBC, complete blood count; cdk, cyclin-dependent kinase; CPC, chromosomal passenger complex; E, embryonic day; HE, hematoxylin and eosin; IAP, inhibitor of apoptosis protein; INCENP, inner centromere protein; pI-pC, polyinosinic-polycytidylic acid; RNAi, RNA interference.


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