Nucleophosmin regulates cell cycle progression and stress response in hematopoietic stem/progenitor cells

June Li, Daniel P. Sejas, Reena Rani, Tara Koretsky, Grover C. Bagby, Qishen Pang

    Research output: Contribution to journalArticle

    39 Scopus citations

    Abstract

    Nucleophosmin (NPM) is a multifunctional protein frequently overexpressed in actively proliferating cells. Strong evidence indicates that NPM is required for embryonic development and genomic stability. Here we report that NPM enhances the proliferative potential of hematopoietic stem cells (HSCs) and increases their survival upon stress challenge. Both short term liquid culture and clonogenic progenitor cell assays show a selective expansion of NPM-overexpressing HSCs. Interestingly, HSCs infected with NPM retrovirus show significantly reduced commitment to myeloid differentiation compared with vector-transduced cells, and majority of the NPM-overexpressing cells remains primitive during a 5-day culture. Bone marrow transplantation experiments demonstrate that NPM promotes the self-renewal of long term repopulating HSCs while attenuated their commitment to myeloid differentiation. NPM overexpression induces rapid entry of HSCs into the cell cycle and suppresses the expression of several negative cell cycle regulators that are associated with G 1-to-S transition. NPM knockdown elevates expression of these negative regulators and exacerbates stress-induced cell cycle arrest. Finally, overexpression of NPM promotes the survival and recovery of HSCs and progenitors after exposure to DNA damage, oxidative stress, and hematopoietic injury both in vivo and in vitro. DNA repair kinetics study suggests that NPM has a role in reducing the susceptibility of chromosomal DNA to damage rather than promoting DNA damage repair. Together, these results indicate that NPM plays an important role in hematopoiesis via mechanisms involving modulation of HSC/progenitor cell cycle progression and stress response.

    Original languageEnglish (US)
    Pages (from-to)16536-16545
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume281
    Issue number24
    DOIs
    StatePublished - Jun 16 2006

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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