4.7 Article

HMGB1: an important regulator of myeloid differentiation and acute myeloid leukemia as well as a promising therapeutic target

期刊

JOURNAL OF MOLECULAR MEDICINE-JMM
卷 99, 期 1, 页码 107-118

出版社

SPRINGER HEIDELBERG
DOI: 10.1007/s00109-020-01998-5

关键词

HMGB1; AML; Myeloid differentiation; TGFBI; Chidamide

资金

  1. National Natural Science Foundation of China [81700099]
  2. Science and Technology Program of Chinese Traditional Medicine from Shandong Province [2019-0485]
  3. Supporting Fund for Teachers' research of Jining Medical University [JYFC2018FKJ025, JYFC2018FKJ112, JYFC2018FKJ033, JYFC2019FKJ194]
  4. Research Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University [JYHL2018FM, JYHL2019FZD02, JYHL2019FMS06]
  5. PhD Research Foundation of Affiliated Hospital of Jining Medical University [2016-BS-003]
  6. Nursery research program of Affiliated Hospital of Jining Medical University [MP-ZD2019-004, MP-MS-2019-007]

向作者/读者索取更多资源

This study demonstrates that HMGB1 is overexpressed in AML patients, promoting leukemia pathogenesis and progression by inhibiting apoptosis, enhancing proliferation, and inducing myeloid differentiation blockade. TGFBI is identified as a potential downstream target of HMGB1. The HDAC inhibitor chidamide shows promise in AML therapy by downregulating HMGB1 expression and promoting differentiation, apoptosis, and inhibiting proliferation of AML cells.
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 messages HMGB1 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.

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