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

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.

PPAR Gamma-Regulated MicroRNA 199a-5p Underlies Bone Marrow Adiposity in Aplastic Anemia.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation has been implicated in the fatty bone marrow and defective hematopoiesis of aplastic anemia (AA). However, the underlying molecular mechanism remains to be investigated. In this study, we found that microRNA 199a-5p (miR-199a-5p) exhibits significantly higher expression in AA BM-MSCs compared with the normal control and is demonstrated to facilitate adipogenic differentiation of BM-MSCs through lentivirus-mediated miR-199a overexpression. Mechanistic investigation reveals that miR-199a-5p could be regulated by PPAR gamma (PPARγ) in a transcription-independent manner and regulates adipogenic differentiation by targeting the expression of transforming growth factor beta induced (TGFBI), which is subsequently validated as a negative regulator of adipogenesis. Besides, the positive correlation between PPARγ and miR-199a-5p expression as well as the inverse relationship between miR-199a-5p and TGFBI expression in normal and AA BM-MSCs was observed. Altogether, our work demonstrates that PPARγ-regulated miR-199a-5p promotes adipogenesis of BM-MSCs by inhibiting TGFBI expression, which might be a novel mechanism underlying the bone marrow adiposity in AA, and provides promising therapeutic targets for AA treatment.

[Relationship between Quantitative Monitoring of WT1 Gene and Prognosis in Patients with Acute Leukemia].

OBJECTIVE: To investigate the exprassion of WT1 gene in patients with adult acute myeloid leukemia (AML) and its clinical significance. METHODS: Sixty-three newly diagnosed patients with acute myeloid leukemia were selected. Quantitative RT-PCR was used to detect the expression of WT1 gene in the 63 AML patients and 20 non-AML controls. RESULTS: WT1 gene was highly expressed in AML patents and its expression in the low-risk group was significantly lower than that in middle-risk group and high-risk group (P<0.05), and no significant difference of WT1 gene expression between middle-risk and high-risk group was observed. In the patients of middle-risk and high-risk patients, the expression of WT1 gene in the remission group was significantly lower than that in the patients of non-remission after treatment (P<0.05). The non-remission patients after first treatment in middle-risk and high-risk group were treated with second induction therapy. After second induction therapy, the WT1 expression in remission patients was significantly decreased (P<0.05) in comparison with that in patients still in non-remission. There was a negative correlation between WT1 expression and the 2-year overall survival rate in the newly diagnosed middle and high-risk AML patients. CONCLUSION: The detection of WT1 gene expression can help to divide AML patients into low-/middle-/high-risk groups and to evaluate therapeutic response and clinical prognosis in middle and high-risk AML patients.

Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis.

Aplastic anaemia (AA) is a life-threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM-derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM-MSCs through lentivirus-mediated ZFP36L1 knock-down and overexpression assay. Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3'-untranslated region bears adenine-uridine-rich elements was verified as a direct downstream target of ZFP36L1, and knock-down of PPARGC1B impaired the adipogenesis of AA BM-MSCs. Collectively, our work demonstrated that ZFP36L1-mediated post-transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM-MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.

Cycloartenol exerts anti-proliferative effects on Glioma U87 cells via induction of cell cycle arrest and p38 MAPK-mediated apoptosis.

PURPOSE: Gliomas are destructive malignancies affecting mainly the central nervous system. Gliomas constitute around 50% of all the central nervous system tumors. The purpose of this study was to examine the anticancer activity of cycloartenol against the glioma U87 cells and to investigate the underlying mechanisms. METHODS: MTT and colony formation assay were used to determine the proliferation rate. Acridine orange/ethidium bromide (AO/EB) and annexin V/propidium iodide (PI) were used to determine apoptosis and cell cycle analysis was carried out by western blotting. Cell migration was checked by cell migration assay and immunoblotting was used for checking protein expressions. RESULTS: The results revealed that cycloartenol inhibited the proliferation and the colony formation potential of the glioma U87 cells in a concentration-dependent manner. The antiproliferative effects were found to be due to induction of Sub-G1 cell cycle arrest and triggering of apoptosis. These effects were found to be dose-dependent. Cycloartenol also caused significant alteration in the expression of Bax and Bcl-2. Furthermore, cycloartenol inhibited the migration of glioma cells and suppressed the phosphorylation of the p38 MAP kinase. CONCLUSION: These findings indicate that cycloartenol may prove beneficial in the treatment of glioma and warrants further investigation.

Acute immune thrombocytopenic purpura as adverse reaction to oral polio vaccine (OPV).

A case of acute immune thrombocytopenic purpura following oral polio vaccine (OPV) is reported. An 82-d-old infant developed purpura at the same day after the second dose of oral polio vaccine. Until the time of hospital admission, the male infant had been in good health and had not received any drugs, and the possible causes of this condition were excluded. His platelet count was 13×10(9)/L. Platelet-associated IgG was elevated, but the amount of megakaryocytes in bone marrow aspirates was within the normal range, suggesting immune mechanism-associated thrombocytopenia. The infant recovered with the proper treatment within 30 d. Attention should be paid to OPV-associated thrombocytopenia, though it seems to be less frequent than after natural infections.