In:
Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 106, No. 8 ( 2020-07-02), p. 2102-2113
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.
Type of Medium:
Online Resource
ISSN:
1592-8721
,
0390-6078
DOI:
10.3324/haematol.2019.231944
Language:
Unknown
Publisher:
Ferrata Storti Foundation (Haematologica)
Publication Date:
2020
detail.hit.zdb_id:
2186022-1
detail.hit.zdb_id:
2030158-3
detail.hit.zdb_id:
2805244-4