dc.contributor.author | Gutjahr, JC | |
dc.contributor.author | Bayer, E | |
dc.contributor.author | Yu, X | |
dc.contributor.author | Laufer, JM | |
dc.contributor.author | Höpner, JP | |
dc.contributor.author | Tesanovic, S | |
dc.contributor.author | Härzschel, A | |
dc.contributor.author | Auer, G | |
dc.contributor.author | Rieß, T | |
dc.contributor.author | Salmhofer, A | |
dc.contributor.author | Szenes, E | |
dc.contributor.author | Haslauer, T | |
dc.contributor.author | Durand-Onayli, V | |
dc.contributor.author | Ramspacher, A | |
dc.contributor.author | Pennisi, SP | |
dc.contributor.author | Artinger, M | |
dc.contributor.author | Zaborsky, N | |
dc.contributor.author | Chigaev, A | |
dc.contributor.author | Aberger, F | |
dc.contributor.author | Neureiter, D | |
dc.contributor.author | Pleyer, L | |
dc.contributor.author | Legler, DF | |
dc.contributor.author | Orian-Rousseau, V | |
dc.contributor.author | Greil, R | |
dc.contributor.author | Hartmann, TN | |
dc.date.accessioned | 2021-06-21T16:20:37Z | |
dc.date.available | 2020-06-26 | |
dc.date.available | 2021-06-21T16:20:37Z | |
dc.date.issued | 2020-07-02 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/72643 | |
dc.description.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. | en_US |
dc.language | eng | |
dc.publisher | Ferrata Storti Foundation | en_US |
dc.relation.ispartof | Haematologica | |
dc.subject | Acute Myeloid Leukemia | en_US |
dc.subject | Bone Marrow Microenvironment | en_US |
dc.subject | CD44 | en_US |
dc.subject | CD49d/CD29 integrin | en_US |
dc.subject | inside-out signaling | en_US |
dc.title | CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity. | en_US |
dc.type | Article | en_US |
dc.rights.holder | © 2021 by the Ferrata Storti Foundation | |
dc.identifier.doi | 10.3324/haematol.2019.231944 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/32616529 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
dcterms.dateAccepted | 2020-06-26 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |