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

• DOI: 10.1084/jem.20062395
• Publication Date: 2007-06-19T00:53:29Z
• Authors: Cindy G. Leung; Yanfei Xu; Bretton Mularski; Hui Liu; Sandeep Gurbuxani; John D. Crispino
• Keywords: Mice, Knockout; 0301 basic medicine; 0303 health sciences; Genotype; Stem Cells; Survivin; Cell Differentiation; Articles; Exons; Hematopoietic Stem Cells; Polymerase Chain Reaction; Inhibitor of Apoptosis Proteins; 3. Good health; Colony-Forming Units Assay; Mice, Inbred C57BL; Repressor Proteins; Mice; 03 medical and health sciences; Animals; Microtubule-Associated Proteins; Bone Marrow Transplantation

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.