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

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-α) by primary human AML cells. TNF-α induces interleukin 1 beta (IL-1β) production by healthy leukocytes, leading to IL-1β-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.

Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance

“…Importantly, stress associated with the events described above leads to release of HMGB1 (high-mobility group box 1) protein by AML cells, which ultimately triggers the production of IL-1β by healthy leukocytes. 14 has been reported to induce the expression and production of stem cell factor (SCF) by epithelial cells via the mTOR pathway and hypoxic signaling. 15 SCF is a major hematopoietic growth factor that controls AML progression, thus becoming highly oncogenic.…”

“…15 In this way, AML cells employ body systems to produce factors required for their proliferation/ disease progression. 14,15 Taking these results together, it is clear that AML cells implement comprehensive mechanisms to escape immune surveillance and facilitate disease progression. Pharmacological targeting of the biochemical pathways responsible for immune escape will enable the human immune system to potentially cure AML, with the goal of avoiding aggressive chemotherapy and bone marrow transplantation.…”

TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

“…This indirect effect occurs via Hmgb1, which we show to be elaborated downstream of Ifnγ. Hmgb1 is a non-histone chromatin binding protein and a member of the alarmin family (43,44). It is known to function as a mediator of inflammatory processes by binding to its receptors including RAGE and a subset of TLRs (44).…”

T‐bet transcription factor in cardiovascular disease: Attenuation or inflammation factor?

“…In addition, a number of cellular signaling pathways have been identified that contribute to T-bet induced differentiation of Th1 in patients with CVD, and their targeting could provide a new therapeutic strategy in patients (Table 2) to the secretion of VEGF by macrophages and neutrophils Soloviev et al, 2014). It has also been shown that HMGB-1 factor leads to the release of both TNF-α and VEGF; therefore, HMGB-1 is likely to stimulate angiogenesis via TNF-α mediation (Yasinska et al, 2018).…”