Julia C. Gutjahr, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Elisabeth Bayer, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Xiaobing Yu, Karlsruhe Institute of Technology, Institute of Toxicology and Genetics
Julia M. Laufer, Biotechnology Institute Thurgau (BITg) at the University of Konstanz
Jan P. Höpner, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Suzana Tesanovic, Department Biosciences, Paris-Lodron University of Salzburg
Andrea Härzschel, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg
Georg Auer, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Tanja Rieß, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Astrid Salmhofer, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Eva Szenes, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Theresa Haslauer, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Valerie Durand-Onayli, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Andrea Ramspacher, Department Biosciences, Paris-Lodron University of Salzburg
Sandra P. Pennisi, Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg
Marc Artinger, Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland
Nadja Zaborsky, 1Laboratory for Immunological and Molecular Cancer Research
Alexandre Chigaev, Department of Pathology and Cancer Center, University of New Mexico
Fritz Aberger, Department Biosciences, Paris-Lodron University of Salzburg
Daniel Neureiter, nstitute of Pathology, Paracelsus Medical University Salzburg
Lisa Pleyer, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Daniel F. Legler, Biotechnology Institute Thurgau (BITg) at the University of Konstanz
Veronique Orian-Rousseau, Karlsruhe Institute of Technology, Institute of Toxicology and Genetics
Richard Greil, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg
Tanja N. Hartmann, 3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg

Document Type

Article

Publication Date

8-1-2021

Abstract

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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