Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice

• Published in: Blood Vol. 118; no. 9; pp. 2454 - 2461
• Main Authors: Ng, Ashley P., Loughran, Stephen J., Metcalf, Donald, Hyland, Craig D., de Graaf, Carolyn A., Hu, Yifang, Smyth, Gordon K., Hilton, Douglas J., Kile, Benjamin T., Alexander, Warren S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-09-2011; Americain Society of Hematology
• Subjects: Animals; Biological and medical sciences; Bone Marrow Transplantation; Cell Division; Colony-Forming Units Assay; Gene Expression Regulation; Genes, Reporter; Hematologic and hematopoietic diseases; Hematopoiesis - genetics; Hematopoiesis - physiology; Hematopoietic Stem Cells - cytology; Heterozygote; Medical sciences; Mice; Mice, Inbred C57BL; Mutation, Missense; Oncogene Proteins - genetics; Oncogene Proteins - physiology; Radiation Chimera; Receptors, Thrombopoietin - genetics; Receptors, Thrombopoietin - physiology; Transcription Factors; Transcriptional Regulator ERG; Hematology; Stem cell; Rodentia; Hematopoietic cell; Stress; Vertebrata; Self renewal; Mammalia; Mouse; Hematopoiesis; Animal; C-Onc gene; Protooncogene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-03-344739

Hematopoietic stem cells (HSCs) are rare residents of the bone marrow responsible for the lifelong production of blood cells. Regulation of the balance between HSC self-renewal and differentiation is central to hematopoiesis, allowing precisely regulated generation of mature blood cells at steady state and expanded production at times of rapid need, as well as maintaining ongoing stem cell capacity. Erg, a member of the Ets family of transcription factors, is deregulated in cancers; and although Erg is known to be required for regulation of adult HSCs, its precise role has not been defined. We show here that, although heterozygosity for functional Erg is sufficient for adequate steady-state HSC maintenance, Erg+/Mld2 mutant mice exhibit impaired HSC self-renewal after bone marrow transplantation or during recovery from myelotoxic stress. Moreover, although mice functionally compromised for either Erg or Mpl, the receptor for thrombopoietin, a key regulator of HSC quiescence, maintained sufficient HSC activity to sustain hematopoiesis, Mpl−/−Erg+/Mld2 compound mutant mice displayed exacerbated stem cell deficiencies and bone marrow failure. Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self-renewal at times of high HSC cycling.