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The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis Tsapogas, Panagiotis; Mooney, Ciaran; Brown, Geoffrey; Rolink, Antonius

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The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis Tsapogas, Panagiotis; Mooney, Ciaran; Brown, Geoffrey; Rolink, Antonius University of Birmingham The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis Tsapogas, Panagiotis; Mooney, Ciaran; Brown, Geoffrey; Rolink, Antonius DOI: 10.3390/ijms18061115 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Tsapogas, P, Mooney, C, Brown, G & Rolink, A 2017, 'The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis', International Journal of Molecular Sciences, vol. 18, no. 6, pp. 1115. https://doi.org/10.3390/ijms18061115 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Sep. 2021 International Journal of Molecular Sciences Review The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis Panagiotis Tsapogas 1,*, Ciaran James Mooney 2, Geoffrey Brown 2,3 and Antonius Rolink 1 1 Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Mattenstrasse 28, Basel 4058, Switzerland; [email protected] 2 Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edbgaston, Birmingham B15 2TT, UK; [email protected] (C.J.M.); [email protected] (G.B.) 3 Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edbgaston, Birmingham B15 2TT, UK * Correspondence: [email protected]; Tel.: +41-61-2075-072; Fax: +41-61-2075-070 Academic Editor: Ewa Marcinkowska Received: 27 April 2017; Accepted: 19 May 2017; Published: 24 May 2017 Abstract: The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed. Keywords: Flt3; hematopoiesis; acute myeloid leukemia (AML); cytokines; Flt3 with internal tandem duplications (FLT3-ITD) 1. Introduction Leukemias occur as a result of the de-regulation of normal hematopoiesis, as evidenced by the significant number of genes important for hematopoietic development that are mutated in leukemias. Therefore, understanding how hematopoiesis is regulated is of utmost importance for the elucidation of the mechanisms that lead to the blood cell malignancies. Cytokines are important regulators of hematopoietic development: they transfer extra-cellular signals to cells to affect their survival, proliferation, differentiation and maturation [1]. The cytokine “Fms-like tyrosine kinase 3 ligand” (hereafter FL) represents a typical example of a hematopoietic cytokine whose receptor is often found to be mutated or over-expressed in leukemias. Therefore, there has been a great deal of attention on the precise role of FL in hematopoiesis. In this review we will give a general outline of our current knowledge of the role of FL in normal and malignant hematopoiesis and will briefly discuss recent findings from us and others that offer new insights on how FL regulates the generation of blood cells. Furthermore, the potential relevance of these findings to the role of FL in hematopoietic malignancies will be discussed. Int. J. Mol. Sci. 2017, 18, 1115; doi:10.3390/ijms18061115 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 1115 2 of 23 2. FL and Its Receptor, Flt3 To date, only one receptor for the cytokine FL has been identified; Fms-like tyrosine kinase 3 (also known as Flk2/CD135; hereafter Flt3). The murine receptor was the first to be identified and cloned by two groups independently [2–4], and soon after its human homologue was cloned [5]. Flt3 belongs to the class III receptor tyrosine kinase group of receptors, which also contains other cytokine receptors, such as the platelet-derived growth factor receptor (PDGF) and c-kit, the receptor for Stem Cell Factor (SCF). Flt3 shows a high sequence and structural homology to these receptors, containing an extra-cellular part with 5 immunoglobulin-like domains, a transmembrane domain and a cytoplasmic region consisting of a juxta-membrane domain followed by two tyrosine kinase domains [6]. The pattern of expression of Flt3 observed in early studies was indicative of its potential importance in hematopoiesis, as it was found to be expressed specifically by early hematopoietic progenitors that contain some degree of stem cell activity, while it was not expressed by more mature blood cell populations [2,3]. In 1993, murine FL was cloned and characterized as a transmembrane protein that can be secreted and, upon binding to Flt3, can stimulate the proliferation of Flt3+ bone marrow and foetal liver progenitors [7,8]. Soon after the human FL was cloned; interestingly, it was shown to be able to bind to murine Flt3 and activate its downstream signaling [9]. Binding of FL to Flt3 leads to homodimerization of the receptor and subsequent conformational changes that result in phosphorylation of the tyrosine kinase domains. This activation of the receptor occurs rapidly and is followed by an equally rapid internalization and degradation of the receptor homodimer [10]. Downstream signaling pathways that are activated by FL-Flt3 binding were studied even before FL was cloned, using a chimeric Flt3 receptor containing the extracellular part of Colony Stimulating Factor 1 receptor (CSF-1R) [11,12]. Subsequent experiments using the native receptor have confirmed some of the initial findings and revealed that Flt3 activation leads to phosphorylation of Src-homology 2 containing proteins (SHC), which directly interact with proteins such as Grb2, Gab2, SHIP, eventually leading to activation of the Ras/MEK/Erk and PI3K pathways [13–16]. Human FLT3 in particular has been shown to bind additionally to tyrosine phosphatase SHP2 and the proto-oncogene CBL, also members of the PI3K pathway [15,17,18]. In addition, Flt3 has been shown to activate Stat3 [19,20] and Stat5a [21] signaling mediators. However, caution should be exercised when interpreting these findings on Flt3 signaling, as most of the above data are derived from work using cell lines, while additional complexity comes from the fact that downstream signaling pathways activated by Flt3 seem to be highly cell-context dependent. The cloning of FL allowed the investigation of its function and early studies focused mainly on assessing its role in supporting the growth and differentiation of hematopoietic progenitors in vitro. Several of these studies demonstrated that FL has a limited effect on the growth of hematopoietic progenitors when used alone, but it is very potent in synergizing with other hematopoietic cytokines, such as SCF, IL-3, IL-6, Granulocyte-Macrophage Colony stimulating Factor (GM-CSF), Granulocyte Colony Stimulating Factor (G-CSF) and IL-11, to promote the generation of primarily myeloid cell containing colonies [22–28]. There was no significant effect of FL as to promoting the in vitro generation of cells of the erythroid [25] or megakaryocyte lineages [22]. In addition, FL was shown to significantly enhance the in vitro generation of B cells, again mainly in combination with the cytokines SCF and IL-7 [26,29–31]. A similar picture of the in vitro effect of FL emerged from studies using human hematopoietic progenitors [23,32,33]. The synergistic effect of FL with other hematopoietic cytokines was a clear conclusion from these experiments. However, studies have been limited both by the lack of markers that could be used to isolate progenitors at different developmental stages and by the use of an exclusively in vitro approach to determine cell behavior. Important insights on the role of FL came from the generation of knock-out mouse models. Initial analysis of mice with targeted deletion of the Flt3 gene showed no significant perturbations in hematopoiesis, apart from a reduction in the numbers of early B cell progenitors and defective repopulation capacity of Flt3−/− bone marrow cells upon transplantation into irradiated hosts [34]. In contrast, mice lacking FL showed a more pronounced phenotype, with a reduced overall generation Int.
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