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      The Possible Importance of β3 Integrins for Leukemogenesis and Chemoresistance in Acute Myeloid Leukemia

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          Abstract

          Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy where the immature leukemia cells communicate with neighboring cells through constitutive cytokine release and through their cell surface adhesion molecules. The primary AML cells express various integrins. These heterodimeric molecules containing an α and a β chain are cell surface molecules that bind extracellular matrix molecules, cell surface molecules and soluble mediators. The β3 integrin (ITGB3) chain can form heterodimers only with the two α chains αIIb and αV. These integrins are among the most promiscuous and bind to a large number of ligands, including extracellular matrix molecules, cell surface molecules and soluble mediators. Recent studies suggest that the two β3 integrins are important for leukemogenesis and chemosensitivity in human AML. Firstly, αIIb and β3 are both important for adhesion of AML cells to vitronectin and fibronectin. Secondly, β3 is important for the development of murine AML and also for the homing and maintenance of the proliferation for xenografted primary human AML cells, and for maintaining a stem cell transcriptional program. These last effects seem to be mediated through Syk kinase. The β3 expression seems to be regulated by HomeboxA9 (HoxA9) and HoxA10, and the increased β3 expression then activates spleen tyrosine kinase (Syk) and thereby contributes to cytokine hypersensitivity and activation of β2 integrins. Finally, high integrin αV/β3 expression is associated with an adverse prognosis in AML and decreased sensitivity to the kinase inhibitor sorafenib; this integrin can also be essential for osteopontin-induced sorafenib resistance in AML. In the present article, we review the experimental and clinical evidence for a role of β3 integrins for leukemogenesis and chemosensitivity in AML.

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          Most cited references76

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          Integrin ligands at a glance.

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            The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.

            Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/beta-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML.
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              Ligand binding to integrins.

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                15 January 2018
                January 2018
                : 19
                : 1
                : 251
                Affiliations
                [1 ]Section for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; silje.johansen@ 123456helse-bergen.no (S.J.); annette.brenner@ 123456k2.uib.no (A.K.B.); hakon.reikvam@ 123456k2.uib.no (H.R.)
                [2 ]Section for Hematology, Institute of Clinical Science, University of Bergen, 5007 Bergen, Norway; sushma.bartaula@ 123456iko.uib.no
                Author notes
                [* ]Correspondence: Oystein.Bruserud@ 123456helse-bergen.no ; Tel.: +47-55-97-50-00; Fax: +47-55-97-29-50
                Article
                ijms-19-00251
                10.3390/ijms19010251
                5796198
                29342970
                29523f71-b7f4-45d0-aaef-572818e257af
                © 2018 by the authors.

                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
                : 30 November 2017
                : 08 January 2018
                Categories
                Review

                Molecular biology
                acute myeloid leukemia,integrin,beta3
                Molecular biology
                acute myeloid leukemia, integrin, beta3

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