Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1

• Published in: Leukemia Vol. 29; no. 2; pp. 433 - 440
• Main Authors: Fukuda, S, Hoggatt, J, Singh, P, Abe, M, Speth, J M, Hu, P, Conway, E M, Nucifora, G, Yamaguchi, S, Pelus, L M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2015; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/31; 38/61; 42/44; 45/77; 631/532/1542; 64/110; 82/80; Alleles; Analysis; Animals; Apoptosis; Bone Marrow Cells - cytology; Cancer; Cancer Research; Cell Cycle; Cell Proliferation; Clonal deletion; Control; Critical Care Medicine; Deletion; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; GATA2 Transcription Factor - metabolism; Gene Deletion; Gene expression; Gene Expression Regulation, Leukemic; Genes; Genetic aspects; Health aspects; Hematology; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Homeodomain Proteins - metabolism; Humans; IAP protein; Inhibitor of Apoptosis Proteins - genetics; Intensive; Internal Medicine; Intracellular Signaling Peptides and Proteins - metabolism; MDS1 and EVI1 Complex Locus Protein; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Molecular targeted therapy; Oligonucleotide Array Sequence Analysis; Oncology; Oncology, Experimental; original-article; Phenotype; Physiological aspects; Pre-B-Cell Leukemia Transcription Factor 1; Progenitor cells; Proto-Oncogenes - genetics; Repressor Proteins - genetics; Retroviridae - genetics; Stem cell transplantation; Stem cells; Survival; Survivin; Target recognition; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transplantation; United States; Japan
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.183

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 HSCs and hematopoietic progenitor cells. 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-1 transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.