High-mobility group box 1 protein and hematologic malignancies with severe inflammation: therapeutic intervention with recombinant thrombomodulin

Abstract

High-mobility group box 1 protein (HMGB1), one of the best characterized damage-associated molecular pattern (DAMP) molecules, has pleiotropic eff ects both inside and outside the cell. In the cell nucleus, HMGB1 bends DNA, and promotes protein assembly on specifi c DNA targets. In the extracellular milieu, HMGB1 acts as a signal of tissue damage. HMGB1 is passively released from necrotic or damaged cells and actively secreted by infl ammatory cells. Extracellular HMGB1 can bind to cell surface receptors – receptor for advanced glycation end products (RAGE) or toll-like receptors (TLR2, TLR4, and TLR9) – and promotes infl ammation, immune responses and tissue regeneration [1,2]. HMGB1 has been implicated in various disease states, including sepsis, ischemia – reperfusion, arthritis, neurodegeneration and cancer. In addition, HMGB1, along with other intracellular factors released from tumor cells induced by chemotherapy (CT) or radiotherapy (RT), is a component of the tumor microenvironment [3]. In this issue of Leukemia and Lymphoma , Inoue and colleagues used serum HMBG1 levels to demonstrate the effi cacy of recombinant human thrombomodulin (rhTM) treatment in patients with hematologic malignancies complicated by systemic infl ammatory response syndrome (SIRS) and disseminated intravascular coagulation (DIC). Th is pilot study included 54 patients, classifi ed into three groups according to their disease status after CT (group 1: 13 patients, complete remission; group 2: 16 patients, no remission; group 3: 25 patients, no remission, SIRS during CT DIC). Th e results of the study demonstrated signifi cantly elevated serum HMBG1 levels in group 3 compared to groups 1 and 2. In addition, 17 patients (group 3), complicated by DIC, received rhTM, and 12 of them showed clinical improvement and remarkable amelioration of serum HMBG1 levels. Although the study has limitations, the report by Inoue et al . provides new/additional information about the management of severe infl ammation in patients with hematologic malignancies [4]. It is probably correct to consider that the increased serum HMBG1 levels were associated with severe infl ammation, and consisted mainly of the active secretion from activated infl ammatory cells and/or the accumulation of HMBG1 passively released from necrotic cells [2]. Furthermore, the clinical and laboratory responses to rhTM treatment in patients complicated by DIC suggest the effi cacy of this anticoagulant agent. rhTM is a protein homologous to the extracellular domains of TM, with anti-in fl ammatory as well as anticoagulant properties, with fewer bleeding complications [5,6]. In addition, the lectin-like domain of TM sequesters HMGB1 protein [7]. TM also aids the proteolytic cleavage of HMGB1 by thrombin [8]. Th is fi nding underlines an additional anti-infl ammatory role of TM, in which thrombin – TM complexes degrade HMGB1 to a less proinfl ammatory form, and may also explain the decrease of serum HMBG1 levels among patients treated with rhTM [8]. So far, very few clinical investigations on the eff ects of rhTM have been reported, and included patients with hematologic malignancies. Saito et al . used rhTM to perform a multicenter, randomized controlled trial in patients with DIC associated with hematological malignancy or infection. In this trial, 116 patients received rhTM, and the same number of patients received heparin. rhTM treatment resulted in a better DIC resolution than heparin (66.1% vs. 49.9%, respectively). Th e disappearance rates of bleeding symptoms were 35.2% for the rhTM group, and 20.9% for the heparin group. However, the overall mortality was similar between the two groups. Decreases of plasma thrombin – antithrombin complex and D-dimer levels were signifi cantly greater in the rhTM group. Consequently, the results of the trial demonstrated that rhTM therapy was more eff ective and safer than heparin therapy [9]. Its is clear that further basic and clinical studies are needed to understand HMGB1 and its complex eff ects on the immune system, to confi rm its important role in various clinical states and to develop novel therapeutic strategies. In addition, further clinical investigations are necessary to evaluate the eff ect of rhTM on the pathophysiology of sepsisinduced DIC. L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y 21 0. 15 2. 15 0. 28 o n 05 /2 0/ 14