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Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2102-2113
Acute Myeloid Leukemia
CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity
Julia C. Gutjahr,1,2* Elisabeth Bayer,1* Xiaobing Yu,3 Julia M. Laufer4, Jan P. Höpner,1 Suzana Tesanovic,5 Andrea Härzschel,6 Georg Auer,1 Tanja Rieß,1 Astrid Salmhofer,1 Eva Szenes,1 Theresa Haslauer,1 Valerie Durand-Onayli,1 Andrea Ramspacher,5 Sandra P. Pennisi,6 Marc Artinger,4 Nadja Zaborsky,1 Alexandre Chigaev,7 Fritz Aberger,5 Daniel Neureiter,8 Lisa Pleyer,1 Daniel F. Legler,4,9 Veronique Orian-Rousseau,3 Richard Greil1 and Tanja N. Hartmann1,6
1Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Paracelsus Medical University, Cancer Cluster Salzburg, Salzburg, Austria; 2Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 3Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Karlsruhe, Germany; 4Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland; 5Department Biosciences, Paris-Lodron University of Salzburg, Cancer Cluster Salzburg, Salzburg, Austria; 6Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany; 7Department of Pathology and Cancer Center, University of New Mexico, Albuquerque, NM, USA; 8Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria and 9Theodor Kocher Institute, University of Bern, Bern, Switzerland
*JCG and EB contributed equally as co-first authors.
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 in pro- genitor cell adhesion in bone marrow. Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-medi- ated way of inside-out VLA-4 activation. In primary AML bone marrow 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 of 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. As a further consequence, the increased adhesion on VCAM-1 allowed AML cells to bind stromal cells strongly. Thereby, the 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, enhancing AML cell reten- tion in the supportive bone marrow microenvironment.
Introduction
Acute myeloid leukemia (AML) is an aggressive and difficult-to-treat hematologic malignancy, characterized by the accumulation of immature myeloid blasts. Within the bone marrow (BM), AML cells interact and communicate with stromal and immune cells and reprogram mesenchymal stromal cells to selectively support leukemic cells, while simultaneously suppressing normal hematopoiesis.1 These microenvironmental interactions contribute to protect leukemic stem cells from chemotherapeutic drugs, thus allowing residual disease after therapy, ultimately causing relapses.1 A better understanding of the adhesive mechanisms that facilitate
Correspondence:
TANJA N. HARTMANN
tanjanhartmann@gmail.com
Received: July 12, 2019. Accepted: June 26, 2020. Pre-published: July 2, 2020.
https://doi.org/10.3324/haematol.2019.231944
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