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CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity [in press]

Gutjahr, Julia C.; Bayer, Elisabeth; Yu, Xiaobing; Laufer, Julia M.; Höpner, Jan P.; Tesanovic, Suzana; Härzschel, Andrea; Auer, Georg; Rieß, Tanja; Salmhofer, Astrid; Szenes, Eva; Haslauer, Theresa; Durand-Onayli, Valerie; Ramspacher, Andrea; Pennisi, Sandra P.; Artinger, Marc; Zaborsky, Nadja; Chigaev, Alexandre; Aberger, Fritz; Neureiter, Daniel; ... mehr

Adhesive properties of leukemia cells shape the degree of organ infiltration and the extent of leukocytosis. CD44 and the integrin VLA-4, a CD49d/CD29 heterodimer, are important factors of progenitor cell adhesion in bone marrow (BM). Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-mediated way of inside-out VLA-4 activation. In primary AML BM samples from patients and the OCI-AML3 cell line, CD44 engagement by hyaluronan induced inside-out activation of VLA-4 resulting in enhanced leukemia cell adhesion on VCAM-1. This was independent from VLA-4 affinity regulation but based on ligand-induced integrin clustering on the cell surface. CD44-induced VLA-4 activation could be inhibited by the Src family kinase inhibitor PP2 and the multikinase inhibitor midostaurin. In further consequence, the increased adhesion on VCAM-1 allowed AML cells to strongly bind stromal cells. Thereby VLA-4/VCAM-1 interaction promoted activation of Akt, MAPK, NF-kB and mTOR signaling and decreased AML cell apoptosis. Collectively, our investigations provide a mechanistic description of an unusual CD44 function in regulating VLA-4 avidity in AML, supporting AML cell retention in the supportive BM microenvironment.

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DOI: 10.3324/haematol.2019.231944
Zugehörige Institution(en) am KIT Institut für Biologische und Chemische Systeme (IBCS)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2020
Sprache Englisch
Identifikator ISSN: 0390-6078, 1592-8721
KITopen-ID: 1000127084
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in Haematologica
Verlag Ferrata Storti Foundation
Vorab online veröffentlicht am 02.07.2020
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