High mobility group box 1 (HMGB1) acts as an “alarmin” to promote acute myeloid leukaemia progression

Yasinska, Inna M. and Goncalves Silva, Isabel and Sakhnevych, Svetlana S. and Ruegg, Laura and Hussain, Rohanah and Siligardi, Giuliano and Fiedler, Walter and Wellbrock, Jasmin and Bardelli, Marco and Varani, Luca and Raap, Ulrike and Berger, Steffen and Gibbs, Bernhard F. and Fasler-Kan, Elizaveta and Sumbayev, Vadim V. (2018) High mobility group box 1 (HMGB1) acts as an “alarmin” to promote acute myeloid leukaemia progression. OncoImmunology, 7 (6). ISSN 2162-402X. (doi:https://doi.org/10.1080/2162402X.2018.1438109) (Full text available)

Abstract

High mobility group box 1 (HMGB1) is a non-histone protein localised in the cell nucleus, where it interacts with DNA and promotes nuclear transcription events. HMGB1 levels are elevated during acute myeloid leukaemia (AML) progression followed by participation of this protein in triggering signalling events in target cells as a pro-inflammatory stimulus. This mechanism was hypothesised to be employed as a survival pathway by malignant blood cells and our aims were therefore to test this hypothesis experimentally. Here we report that HMGB1 triggers the release of tumour necrosis factor alpha (TNF-?) by primary human AML cells. TNF-? induces interleukin 1 beta (IL-1?) production by healthy leukocytes, leading to IL-1?-induced secretion of stem cell factor (SCF) by competent cells (for example endothelial cells). These results were verified in mouse bone marrow and primary human AML blood plasma samples. In addition, HMGB1 was found to induce secretion of angiogenic vascular endothelial growth factor (VEGF) and this process was dependent on the immune receptor Tim-3. We therefore conclude that HMGB1 is critical for AML progression as a ligand of Tim-3 and other immune receptors thus supporting survival/proliferation of AML cells and possibly the process of angiogenesis.

Item Type: Article
Uncontrolled keywords: Acute myeloid leukaemia, high mobility group box 1, Tim-3, stem cell factor, inflammation
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Vadim Sumbayev
Date Deposited: 26 Mar 2018 15:27 UTC
Last Modified: 13 Jun 2018 11:37 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66541 (The current URI for this page, for reference purposes)
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