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Cited2 is an essential regulator of adult hematopoietic stem cells.

TitleCited2 is an essential regulator of adult hematopoietic stem cells.
Publication TypeJournal Article
Year of Publication2009
AuthorsKranc KR, Schepers H, Rodrigues NP, Bamforth S, Villadsen E, Ferry H, Bouriez-Jones T, Sigvardsson M, Bhattacharya S, Jacobsen SEirik, Enver T
JournalCell Stem Cell
Date Published2009 Dec 4
KeywordsADP-Ribosylation Factors, Adult Stem Cells, Animals, Cell Differentiation, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, Hematopoietic Stem Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, p300-CBP Transcription Factors, Repressor Proteins, RNA, Small Interfering, Trans-Activators, Transcriptional Activation, Tumor Suppressor Protein p53

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.

Alternate JournalCell Stem Cell
PubMed ID19951693
PubMed Central IDPMC2828538
Grant ListG0501838 / / Medical Research Council / United Kingdom
G0801073 / / Medical Research Council / United Kingdom
MC_U137973817 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
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