Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance

Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance.

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Item Type: Article
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
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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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