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The regulatory pathways necessary for the maintenance of adult hematopoietic stem cells (HSCs) remain poorly defined. By using loss-of-function approaches, we report a selective and cell-autonomous requirement for the p300/CBP-binding transcriptional coactivator Cited2 in adult HSC maintenance. Conditional deletion of Cited2 in the adult mouse results in loss of HSCs causing multilineage bone marrow failure and increased lethality. In contrast, conditional ablation of Cited2 after lineage specification in lymphoid and myeloid lineages has no impact on the maintenance of these lineages. Additional deletion of Ink4a/Arf (encoding p16(Ink4a) and p19(Arf)) or Trp53 (encoding p53, a downstream target of p19(Arf)) in a Cited2-deficient background restores HSC functionality and rescues mice from bone marrow failure. Furthermore, we show that the critical role of Cited2 in primitive hematopoietic cells is conserved in humans. Taken together, our studies provide genetic evidence that Cited2 selectively maintains adult HSC functions, at least in part, via Ink4a/Arf and Trp53.

Original publication

DOI

10.1016/j.stem.2009.11.001

Type

Journal article

Journal

Cell stem cell

Publication Date

12/2009

Volume

5

Pages

659 - 665

Addresses

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK. kamil.kranc@ndm.ox.ac.uk

Keywords

Hematopoietic Stem Cells, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, ADP-Ribosylation Factors, Trans-Activators, Repressor Proteins, RNA, Small Interfering, Cell Differentiation, Cell Lineage, Tumor Suppressor Protein p53, Cyclin-Dependent Kinase Inhibitor p16, p300-CBP Transcription Factors, Adult Stem Cells, Transcriptional Activation