Survivin Modulates Genes with Divergent Molecular Functions and Regulates Proliferation of Hematopoietic Stem Cells through Evi-1

The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs and Survivin deletion in mice resulted in significantly reduced total marrow HSC and progenitor cells (HPC). Transcriptional analysis of Survivin(−/−) HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin −/− HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.