Fancd2 and p21 function independently in maintaining the size of hematopoietic stem and progenitor cell pool in mice

• Published in: Stem cell research 2013-09, Vol.11 (2), p.687-692
• Main Authors: Zhang, Qing-Shuo, Watanabe-Smith, Kevin, Schubert, Kathryn, Major, Angela, Sheehan, Andrea M., Marquez-Loza, Laura, Newell, Amy E. Hanlon, Benedetti, Eric, Joseph, Eric, Olson, Susan, Grompe, Markus
• Format: Article
• Language: English
• Subjects: Animals; Cell Size; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi Anemia - pathology; Fanconi Anemia Complementation Group D2 Protein - genetics; Fanconi Anemia Complementation Group D2 Protein - metabolism; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Stem Cells - cytology; Stem Cells - metabolism
• ISSN: 1873-5061; 1876-7753
• DOI: 10.1016/j.scr.2013.04.010

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. •Hyperactive p53 activity in Fanconi anemia stem cells is not mediated by p21.•p21 is important for maintaining the normal size of HSPC pool.•Fancd2 and p21 work independently in maintain normal hematopoiesis.