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Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation.

ABSTRACT: Overactive p53 has been proposed as an important pathophysiological factor for bone marrow failure syndromes, including Fanconi anemia (FA). Here, we report a p53-dependent effect on hematopoietic stem and progenitor cell (HSPC) proliferation in mice deficient for the FA gene Fanca. Deletion of p53 in Fanca-/- mice leads to replicative exhaustion of the hematopoietic stem cell (HSC) in transplant recipients. Using Fanca-/- HSCs expressing the separation-of-function mutant p53515C transgene, which selectively impairs the p53 function in apoptosis but keeps its cell-cycle checkpoint activities intact, we show that the p53 cell-cycle function is specifically required for the regulation of Fanca-/- HSC proliferation. Our results demonstrate that p53 plays a compensatory role in preventing FA HSCs from replicative exhaustion and suggest a cautious approach to manipulating p53 signaling as a therapeutic utility in FA.

SUBMITTER: Li X

PROVIDER: S-EPMC5830889 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Cell-Cycle-Specific Function of p53 in Fanconi Anemia Hematopoietic Stem and Progenitor Cell Proliferation.

Li Xiaoli X Wilson Andrew F AF Du Wei W Pang Qishen Q

Stem cell reports 20180104 2

Overactive p53 has been proposed as an important pathophysiological factor for bone marrow failure syndromes, including Fanconi anemia (FA). Here, we report a p53-dependent effect on hematopoietic stem and progenitor cell (HSPC) proliferation in mice deficient for the FA gene Fanca. Deletion of p53 in Fanca<sup>-/-</sup> mice leads to replicative exhaustion of the hematopoietic stem cell (HSC) in transplant recipients. Using Fanca<sup>-/-</sup> HSCs expressing the separation-of-function mutant p ...[more]

PMID: 29307578

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