Abstract
High mobility group box 1 (HMGB1) is a non-histone nuclear protein which has been intensively studied in various physiological and pathological processes including leukemia. Here in this study, we further demonstrated that HMGB1 presents higher expression in the bone marrow mononuclear cells of acute myeloid leukemia (AML) patients compared with the normal controls and contributes to the AML pathogenesis and progression by inhibiting apoptosis, facilitating proliferation, and inducing myeloid differentiation blockade of AML cells. Mechanistic investigation revealed that transforming growth factor beta-induced (TGFBI) acts as a potential downstream target of HMGB1 and lentivirus-mediated knockdown of TGFBI expression impaired phorbol-12-myristate-13-acetate (PMA) and all-trans retinoic acid (ATRA)–induced myeloid differentiation of AML cell lines. On the other hand, chidamide, an orally histone deacetylase inhibitor, decreases HMGB1 expression significantly in AML cells with concomitant upregulation of TGFBI expression, and confers therapeutic effect on AML by inducing cell differentiation, apoptosis and inhibiting cell proliferation. In conclusion, our findings provide additional insights that HMGB1 is a promising therapeutic target of AML, and also present experimental evidence for the clinical application of chidamide as a novel agent in AML therapy by downregulating HMGB1 expression.Key messagesHMGB1 induces cell proliferation and myeloid differentiation blockade and inhibits apoptosis of AML cells.TGFBI acts as a potential target of HMGB1.Chidamide, a selective HDAC inhibitor, confers promising therapeutic effect for AML via downregulating HMGB1 expression.
Highlights
The granulocytic and macrophage-like differentiation and maturation constitute the important part of myeloid differentiation which is a highly orchestrated process regulated by transcriptional factors (such as PU.1 and CCAAT/enhancerbinding protein(C/EBP)α) [1], cytokines (in particular granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3)) [2], non-coding RNAs [3, 4], and RNA-binding proteins [5]
High mobility group box 1 (HMGB1) is defined as one of the significantly differential genes (Fig. 1a), and further Western blot analyses validated its higher expression in the bone marrow mononuclear cells (MNCs) of acute myeloid leukemia (AML) patients compared with the normal controls (Fig. 1b), which is in accordance with the findings previously reported [18] and implies important role of HMGB1 in the leukemogenesis of AML
Western blot analyses revealed that lenti-shHMGB1 infection remarkably decreased HMGB1 expression which significantly inhibits proliferation and facilitate apoptosis of AML cells (Fig. 2a–d) as compared with the lenti-control infection
Summary
The granulocytic and macrophage-like differentiation and maturation constitute the important part of myeloid differentiation which is a highly orchestrated process regulated by transcriptional factors (such as PU. and CCAAT/enhancerbinding protein(C/EBP)α) [1], cytokines (in particular granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3)) [2], non-coding RNAs (miR-29a, miR-142-3p, and lnc-MC, etc.) [3, 4], and RNA-binding proteins [5] Abnormal expression of these regulators can lead to acute myeloid leukemia (AML) which is a malignant hematopoietic neoplasm characterized by arrest of myeloid differentiation, rapid growth, and apoptotic repression of leukemic blasts arisen from the. It is still of great importance and in urgent need to define the key regulator in myeloid differentiation and pathogenesis of AML and develop innovative agents and novel therapeutic strategies for AML treatment
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