Abstract
Identifying physiological roles of specific signaling pathways that regulate hematopoietic stem cell (HSC) functions may lead to new treatment strategies and therapeutic interventions for hematologic disorders. Here, we provide genetic evidence that constitutive activation of NF-κB in HSCs results in reduced pool size, repopulation capacities, and quiescence of HSCs. Global transcriptional profiling and bioinformatics studies identified loss of ‘stemness’ and ‘quiescence’ signatures in HSCs with deregulated NF-κB activation. In particular, gene set enrichment analysis identified upregulation of cyclin dependent kinase- Ccnd1 and down regulation of cyclin dependent kinase inhibitor p57kip2. Interestingly, constitutive activation of NF-κB is sufficient to alter the regulatory circuits of transcription factors (TFs) that are critical to HSC self-renewal and functions. Molecular studies identified Junb, as one of the direct targets of NF-κB in hematopoietic cells. In essence, these studies demonstrate that aberrant activation of NF-κB signals impairs HSC quiescence and functions and alters the ‘TF networks’ in HSCs.
Highlights
Hematopoiesis is a process through which all the blood cells are generated through sequential cell divisions and differentiation of progeny that originate from hematopoietic stem cells (HSCs) (Kondo et al, 2003)
Vav1 promoter has been proven to be largely specific to the hematopoietic lineage, in particular, it is expressed at all stages of hematopoiesis, i.e., from HSCs to terminally differentiated myeloid, erythroid, and lymphoid lineage cells
Our analysis revealed that the HSC ‘stemness’ signature was almost lost in IKK2 containing these serine to glutamate mutations (IKK2CA) LT-HSCs (Figure 4C)
Summary
Hematopoiesis is a process through which all the blood cells are generated through sequential cell divisions and differentiation of progeny that originate from hematopoietic stem cells (HSCs) (Kondo et al, 2003). Decision of HSCs to remain at a quiescent state or enter into an actively proliferating state is controlled by number of factors through both cell intrinsic and extrinsic mechanisms. In response to extrinsic soluble factors; inflammatory cytokines such as interferon (IFN)-α and IFN-γ; growth factors such as granulocyte colony stimulating factor (GCSF), stem cell factor (SCF), and thrombopoietin (TPO); NF-κB Regulates HSC Quiescence cytokines such as transforming growth factor (TGF) -β and tumor necrosis factor (TNF)-α; and chemokines such as the stromal cell derived factor (SDF)-1, HSCs can either enter dormancy or cell cycle (Wilson and Trumpp, 2006; Kiel and Morrison, 2008; Trumpp et al, 2010). A harmony between intrinsic and extrinsic factors is essential for proper maintenance of HSCs in the bone marrow niche
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