Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance.
Full text not available from this repository.Item Type: | Article |
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Status: | Published |
Official URL: | https://doi.org/10.1038/s41467-020-15817-5 |
Journal or Publication Title: | Nature Communications |
Volume: | 11 |
Number: | 1 |
Date: | 2020 |
Divisions: | Gene and Stem Cell Therapy |
Depositing User: | General Admin |
Identification Number: | 10.1038/s41467-020-15817-5 |
ISSN: | 2041-1723 |
Date Deposited: | 04 Jan 2021 03:08 |
Abstract: | The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. We now report in contrast, E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. Using acute myeloid leukemia (AML) mouse models, we show AML blasts release inflammatory mediators that upregulate endothelial niche E-selectin expression. Alterations in cell-surface glycosylation associated with oncogenesis enhances AML blast binding to E-selectin and enable promotion of pro-survival signaling through AKT/NF-κB pathways. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to disease relapse. Absence (in Sele−/− hosts) or therapeutic blockade of E-selectin using small molecule mimetic GMI-1271/Uproleselan effectively inhibits this niche-mediated pro-survival signaling, dampens AML blast regeneration, and strongly synergizes with chemotherapy, doubling the duration of mouse survival over chemotherapy alone, whilst protecting endogenous HSC. |
Creators: | Creators Email Barbier, Valerie UNSPECIFIED Erbani, Johanna UNSPECIFIED Fiveash, Corrine UNSPECIFIED Davies, Julie M. UNSPECIFIED Tay, Joshua UNSPECIFIED Tallack, Michael R. UNSPECIFIED Lowe, Jessica UNSPECIFIED Magnani, John L. UNSPECIFIED Pattabiraman, Diwakar R. UNSPECIFIED Perkins, Andrew C. UNSPECIFIED Lisle, Jessica UNSPECIFIED Rasko, John E. J. UNSPECIFIED Levesque, Jean-Pierre UNSPECIFIED Winkler, Ingrid G. UNSPECIFIED |
Last Modified: | 04 Jan 2021 03:08 |
URI: | https://eprints.centenary.org.au/id/eprint/755 |
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