Necdin, a p53 target gene, regulates the quiescence and response to genotoxic stress of hematopoietic stem/progenitor cells

Abstract

We recently defined a critical role for p53 in regulating the quiescence of adult hematopoietic stem cells (HSCs) and identified necdin as a candidate p53 target gene. Necdin is a growth-suppressing protein and the gene encoding it is one of several that are deleted in patients with Prader-Willi syndrome. To define the intrinsic role of necdin in adult hematopoiesis, in the present study, we transplanted necdin-null fetal liver cells into lethally irradiated recipients. We show that necdin-null adult HSCs are less quiescent and more proliferative than normal HSCs, demonstrating the similar role of necdin and p53 in promoting HSC quiescence during steady-state conditions. However, wild-type recipients repopulated with necdin-null hematopoietic stem/ progenitor cells show enhanced sensitivity to irradiation and chemotherapy, with increased p53-dependent apoptosis, myelosuppression, and mortality. Necdin controls the HSC response to genotoxic stress via both cell-cycle-dependent and cell-cycle-independent mechanisms, with the latter occurring in a Gas2L3-dependent manner. We conclude that necdin functions as a molecular switch in adult hematopoiesis, acting in a p53-like manner to promote HSC quiescence in the steady state, but suppressing p53-dependent apoptosis in response to genotoxic stress. (Blood. 2012;120(8): 1601-1612) IntroductionHematopoietic stem cells (HSCs) can remain quiescent or can enter the cell cycle and either self-renew or differentiate. 1 HSCs divide infrequently, and it has long been thought that the entire HSC pool turns over every few weeks and that HSCs regularly enter and exit the cell cycle. 1,2 This paradigm has been challenged, because 2 functionally distinct HSC populations, dormant HSCs and activated HSCs, have been identified by independent groups of investigators. 3,4 HSC quiescence is likely controlled by both HSC-intrinsic mechanisms and BM microenvironmental factors, with several genes and signaling pathways implicated in this process. 5 Several regulators of the cell-cycle machinery have been shown to play critical regulatory roles in hematopoietic stem/progenitor cell (HSPC) proliferation, including p21, p57, p18, and the D-type cyclins and their catalytic partners Cdk4 and Cdk6. 6-10 HSC cell-fate decisions are also regulated by several transcription factors (eg, Gfi-1, MEF/ELF4, Pbx-1, C-myc, and N-myc). [11][12][13][14] Interestingly, recent studies indicate that tumor-suppressor genes, including PTEN, pRb, PML, APC, and Fbw7, may also play critical roles in maintaining HSCs in a quiescent state. [15][16][17][18][19] In addition to HSC-intrinsic mechanisms, HSC function is regulated by ligand-receptor interactions, including angiopoietin and Tie-2, thrombopoietin and c-Mpl, SCF and c-Kit, and stromal-derived factor 1 (also known as Cxcl12) and Cxcr4. [20][21][22][23] Recently, we defined a critical role for p53 in regulating HSC quiescence and identified necdin as a p53 target gene with a promoter that binds and is transactivated by p53. 24,25 Necdin is a growth-suppressing ...

Epigenetic reprogramming induces the expansion of cord blood stem cells

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Bcl‐2 proteins in development, health, and disease of the hematopoietic system

“…Only recently it was shown that p53 and its target Nectin promoted quiescence of murine HSCs. Loss of p53 led to increased cell cycle entry and a significant increase in LSK cell numbers [143][144][145]. While exit from quiescence was associated with loss of HSC self-renewal and impaired performance in competitive transplantation assays in many genetically modified mice, deficiency of p53 was shown to result in a better engraftment into recipient mice.…”

The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

“…52 Recent mouse studies have also confirmed that Necdin-null adult HSCs are less quiescent and more proliferative than normal. 109 Other targets modulated by p53 during differentiation of HSCs remain to be identified.…”