title: Fancd2 and p21 function independently in maintaining the size of hematopoietic stem and progenitor cell pool in mice.
abstract: Fanconi anemia patients suffer from progressive bone marrow failure. An overactive p53 response to DNA damage contributes to the progressive elimination of Fanconi anemia hematopoietic stem and progenitor cells (HSPC), and hence presents a potential target for therapeutic intervention. To investigate whether the cell cycle regulatory protein p21 is the primary mediator of the p53-dependent stem cell loss, p21/Fancd2 double-knockout mice were generated. Surprisingly double mutant mice displayed even more severe loss of HSPCs than Fancd2(-/-) single mutants. p21 deletion did not rescue the abnormal cell cycle profile and had no impact on the long-term repopulating potential of Fancd2(-/-) bone marrow cells. Collectively, our data indicate that p21 has an indispensable role in maintaining a normal HSPC pool and suggest that other p53-targeted factors, not p21, mediate the progressive elimination of HSPC in Fanconi anemia.
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA. zhangqi@ohsu.edu
authors.forename: Qing-Shuo
authors.initials: QS
authors.lastname: Zhang
authors.forename: Kevin
authors.initials: K
authors.lastname: Watanabe-Smith
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schubert
authors.forename: Angela
authors.initials: A
authors.lastname: Major
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Sheehan
authors.forename: Laura
authors.initials: L
authors.lastname: Marquez-Loza
authors.forename: Amy E Hanlon
authors.initials: AE
authors.lastname: Newell
authors.forename: Eric
authors.initials: E
authors.lastname: Benedetti
authors.forename: Eric
authors.initials: E
authors.lastname: Joseph
authors.forename: Susan
authors.initials: S
authors.lastname: Olson
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000818:Animals; D048429:Cell Size; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein
keywords: CBC; FA; FITC; Fanconi anemia; H&E; HSPC; KSL; cKit(+)Sca1(+)Lin(−); complete blood count; fluorescein isothiocyanate; hematopoietic stem and progenitor cells; hematoxylin and eosin; qPCR; quantitative real-time PCR