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      STAT5A and STAT5B—Twins with Different Personalities in Hematopoiesis and Leukemia

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          Abstract

          The transcription factors STAT5A and STAT5B have essential roles in survival and proliferation of hematopoietic cells—which have been considered largely redundant. Mutations of upstream kinases, copy number gains, or activating mutations in STAT5A, or more frequently in STAT5B, cause altered hematopoiesis and cancer. Interfering with their activity by pharmacological intervention is an up-and-coming therapeutic avenue. Precision medicine requests detailed knowledge of STAT5A’s and STAT5B’s individual functions. Recent evidence highlights the privileged role for STAT5B over STAT5A in normal and malignant hematopoiesis. Here, we provide an overview on their individual functions within the hematopoietic system.

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          IFNalpha activates dormant haematopoietic stem cells in vivo.

          Marieke Essers, Sandra Offner, William E. Blanco-Bose … (2009)
          Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
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            The molecular details of cytokine signaling via the JAK/STAT pathway

            Rhiannon S Morris, Nadia Kershaw, Jeffrey Babon (2018)
            More than 50 cytokines signal via the JAK/STAT pathway to orchestrate hematopoiesis, induce inflammation and control the immune response. Cytokines are secreted glycoproteins that act as intercellular messengers, inducing proliferation, differentiation, growth, or apoptosis of their target cells. They act by binding to specific receptors on the surface of target cells and switching on a phosphotyrosine‐based intracellular signaling cascade initiated by kinases then propagated and effected by SH2 domain‐containing transcription factors. As cytokine signaling is proliferative and often inflammatory, it is tightly regulated in terms of both amplitude and duration. Here we review molecular details of the cytokine‐induced signaling cascade and describe the architectures of the proteins involved, including the receptors, kinases, and transcription factors that initiate and propagate signaling and the regulatory proteins that control it.
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              Mechanisms of Jak/STAT signaling in immunity and disease.

              Alejandro Villarino, Yuka Kanno, John R Ferdinand … (2015)
              More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 04 November 2019
                Publication date Collection: November 2019
                Volume: 11
                Issue: 11
                Electronic Location Identifier: 1726
                Affiliations
                Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 1210 Vienna, Austria; sebastian.kollmann@ 123456vetmeduni.ac.at (S.K.); judith.pickem@ 123456gmail.com (J.P.); Andrea.hoelbl@ 123456vetmeduni.ac.at (A.H.-K.); veronika.sexl@ 123456vetmeduni.ac.at (V.S.)
                Author notes
                [* ]Correspondence: barbara.maurer@ 123456vetmeduni.ac.at ; Tel.: +43-125-077-2940
                [†]

                Equal first author contribution.

                Article
                Publisher ID: cancers-11-01726
                DOI: 10.3390/cancers11111726
                PMC ID: 6895831
                PubMed ID: 31690038
                SO-VID: a0727a3c-5700-410f-8548-2fc4a56474c1
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 September 2019
                Date accepted : 01 November 2019
                Categories
                Subject: Review

                Keywords: stat5a,stat5b,hematopoietic stem cells,stat5bn642h,stat5 mouse models,bcr–abl,leukemia,hematopoiesis
                Data availability:
                Keywords: stat5a, stat5b, hematopoietic stem cells, stat5bn642h, stat5 mouse models, bcr–abl, leukemia, hematopoiesis

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