Cited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells

被引：98

作者：

Kranc, Kamil R. ^{[1
,2
]}

Schepers, Hein ^{[2
]}

Rodrigues, Neil P. ^{[1
]}

Bamforth, Simon ^{[3
]}

Villadsen, Ellen ^{[1
,2
]}

Ferry, Helen ^{[2
]}

Bouriez-Jones, Tiphaine ^{[2
]}

Sigvardsson, Mikael ^{[4
]}

Bhattacharya, Shoumo ^{[5
]}

Jacobsen, Sten Eirik ^{[2
]}

Enver, Tariq ^{[1
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England

[2] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Haematopoiet Stem Cell Lab, Oxford OX3 9DS, England

[3] Newcastle Univ, Int Ctr Life, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[4] Linkoping Univ, Dept Clin & Expt Res, S-58185 Linkoping, Sweden

[5] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

来源：

CELL STEM CELL | 2009年 / 5卷 / 06期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

CREB-BINDING-PROTEIN; MULTIPOTENT PROGENITORS; GENE-EXPRESSION; COACTIVATOR; SURVIVAL; MICE; IDENTIFICATION; MAINTENANCE; DEFECTS; PRODUCT;

D O I：

10.1016/j.stem.2009.11.001

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

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.

引用

页码：659 / 665

页数：7

共 32 条

[1]

Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors [J].