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.
Gutjahr JC, Bayer E, Yu X, Laufer JM, Höpner JP, Tesanovic S, Härzschel A, Auer G, Rieß T, Salmhofer A, Szenes E, Haslauer T, Durand-Onayli V, Ramspacher A, Pennisi SP, Artinger M, Zaborsky N, Chigaev A, Aberger F, Neureiter D, Pleyer L, Legler DF, Orian-Rousseau V, Greil R, Hartmann TN. CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity. Haematologica. 2021 Aug 1;106(8):2102-2113. doi: 10.3324/haematol.2019.231944. PMID: 32616529; PMCID: PMC8327716.