The Thrombopoietin/MPL Pathway in Hematopoiesis and Leukemogenesis

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.26). 06/2011; 112(6):1491-8. DOI: 10.1002/jcb.23089
Source: PubMed


Hematopoietic stem cells (HSC) comprise a small percentage of total hematopoietic cells. Their ability to self-renewal is key to the continuous replenishment of the hematopoietic system with newly formed functional blood cell types while maintaining their multipotential capacity. Understanding the extrinsic signals that are essential to HSC maintenance will provide insights into the regulation of hematopoiesis at its most primitive stage, and with the knowledge applied, will potentially lead to improved clinical transplantation outcomes. In this review, we will summarize the current understanding of the role of the thrombopoietin/MPL signaling pathway in HSC maintenance during adult and fetal hematopoiesis. We will also speculate on the downstream key players in the pathway based on published data, and summarize the role of this pathway in leukemia.

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Available from: James C Mulloy, Feb 27, 2015
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    • "These experiments demonstrated that Mpl is the direct target of VEGF–miR­1 axis in Th2 inflammation. Mpl, the receptor for thrombopoietin, is known for its roles in megakaryopoiesis and hematopoietic stem cell differ­ entiation (Chou and Mulloy, 2011). It is expressed on endo­ thelial cells and progenitors (Cardier and Dempsey, 1998; Amano et al., 2005; Jin et al., 2006; Eguchi et al., 2008) and affects the accumulation of plasma cells in bone marrow and the differentiation of mast cells (Migliaccio et al., 2007; Winter et al., 2010). "
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    ABSTRACT: Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
    Full-text · Article · Sep 2013 · Journal of Experimental Medicine
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    • "c-Mpl/TPO signaling pathway. TPO signals to its receptor, c-Mpl, and induces the downstream signaling cascades: STATs, PI3K, MAPKs, and extracellular signal regulated kinases-1 and -2 (modified from [14, 15]). "
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    ABSTRACT: Hematopoietic stem cells (HSCs) play a key role in hematopoietic system that functions mainly in homeostasis and immune response. HSCs transplantation has been applied for the treatment of several diseases. However, HSCs persist in the small quantity within the body, mostly in the quiescent state. Understanding the basic knowledge of HSCs is useful for stem cell biology research and therapeutic medicine development. Thus, this paper emphasizes on HSC origin, source, development, the niche, and signaling pathways which support HSC maintenance and balance between self-renewal and proliferation which will be useful for the advancement of HSC expansion and transplantation in the future.
    Full-text · Article · Jul 2012
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    • "Initial characterization of c-Mpl-deficient mice showed that they have severe thrombocytopenia but relatively normal levels of other hematological cell types [3]. Subsequently, several research groups identified TPO as the primary ligand for the c-Mpl receptor [4–10] and TPO/Mpl signal transduction was shown to play critical roles in thrombopoiesis, from ex vivo megakaryocyte progenitor expansion and differentiation to in vivo platelet production [4–11]. "
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    ABSTRACT: Thrombopoietin (TPO) is a humoral growth factor originally identified for its ability to stimulate the proliferation and differentiation of megakaryocytes. In addition to its actions on thrombopoiesis, TPO directly modulates the homeostatic potential of mature platelets by influencing their response to several stimuli. In particular, TPO does not induce platelet aggregation per se but is able to enhance platelet aggregation in response to different agonists (“priming effect”). Our research group was actively involved, in the last years, in characterizing the effects of TPO in several human critical diseases. In particular, we found that TPO enhances platelet activation and monocyte-platelet interaction in patients with unstable angina, chronic cigarette smokers, and patients with burn injury and burn injury complicated with sepsis. Moreover, we showed that TPO negatively modulates myocardial contractility by stimulating its receptor c-Mpl on cardiomyocytes and the subsequent production of NO, and it mediates the cardiodepressant activity exerted in vitro by serum of septic shock patients by cooperating with TNF-α and IL-1β. This paper will summarize the most recent results obtained by our research group on the pathogenic role of elevated TPO levels in these diseases and discuss them together with other recently published important studies on this topic.
    Full-text · Article · Apr 2012 · Mediators of Inflammation
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