Cited2 is an essential regulator of adult hematopoietic stem cells.
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.
Kranc
Kamil R
KR
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK. kamil.kranc@ndm.ox.ac.uk
Schepers
Hein
H
Rodrigues
Neil P
NP
Bamforth
Simon
S
Villadsen
Ellen
E
Ferry
Helen
H
Bouriez-Jones
Tiphaine
T
Sigvardsson
Mikael
M
Bhattacharya
Shoumo
S
Jacobsen
Sten Eirik
SE
Enver
Tariq
T
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D053687:Adult Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
C110087:Cited2 protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D020727:ADP-Ribosylation Factors