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T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are characterized by inferior treatment effects, high heterogeneity, poor prognosis, and a lack of specific therapeutic targets and drugs to improve outcome. Disulfiram (DSF) is a drug used to clinically control alcoholism that has recently been shown to be cytotoxic for multiple cancers. However, the underlying effects and mechanisms of DFS treatment in patients with T-cell malignancies are not well characterized. In this study, we report that DSF promotes apoptosis and inhibits the proliferation of malignant T-cell cell lines and primary T-ALL cells. We provide evidence that DSF exerts anticancer activity in T-cell malignancies by targeting the NPL4-mediated ubiquitin–proteasome pathway. Notably, high expression of NPL4 and 2 ubiquitin–proteasome pathway genes, anaphase-promoting complex subunit 1 (ANAPC1) and proteasome 26S subunit ubiquitin receptor, non-ATPase 2 (PSMD2), was significantly associated with unfavorable overall survival (OS) for patients with TCL and T-ALL (p

Background Despite advances in the treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA), its underlying mechanism has not been fully elucidated. The oncogenic microRNA cluster miR-17-92 modulates multiple cellular processes, including survival, proliferation, and apoptosis. However, the role of miR-17-92 and its regulation has not yet been documented for APL. Methods We analyzed miR-17-92 expression in APL samples and cell lines by qRT-PCR. The expression of c-Myc was measured by western blot. Cell differentiation was assessed by measuring the surface CD11b antigen expression by flow cytometry analysis. Results We observed that miR-17-92 was upregulated in APL compared with healthy donors. Furthermore, we demonstrated that expressions of c-Myc and miR-17-92 are markedly suppressed during ATRA-induced NB4 cell differentiation. Importantly, we also demonstrated that miR-17-92 is directly regulated by c-Myc during the granulocytic differentiation of APL cells. Finally, the overexpression of miR-17-5p blocks ATRA-induced differentiation. Conclusions We report abnormal expression of the miR-17-92 cluster in APL cells, which is responsible for the differentiation block in blast cells in APL. In addition, we identified miR-17-92 as a target gene of c-Myc during ATRA-induced granulocytic differentiation.

BACKGROUND Physalin B (PB) from Physalis angulata L. (Solanaceae) is a naturally occurring secosteroid with multiple biological activities, including anti-inflammatory and anticancer activity. However, PB's effects and mechanisms in human gastric cancer (GC) cells are not well characterized. METHODS The undifferentiated GC cell line HGC-27 and semi-differentiated GC cell line SGC-7901 were treated with PB. Cell counting kit-8 (CCK-8) and colony formation assays were performed to evaluate cell viability. Apoptosis and the cell cycle were assessed by Annexin V/PI and PI/RNase DNA staining assays, respectively, and Western blotting was used to evaluate the expression of a protein. RESULTS PB significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. Moreover, PB induced G0/G1 cycle arrest and caspase-dependent apoptosis of HGC-27 cells. Cleaved caspases 8, 3, and 7, poly(ADP)-ribose polymerase (PARP), and the cyclin-dependent kinase (CDK) inhibitor p-Chk2 was induced by PB in HGC-27 cells, while the cell cycle-related proteins cyclin D1, cyclin D3, CDK4, CDK6, cyclin E, and phosphorylated retinoblastoma tumor suppressor protein (p-Rb) were downregulated in a dose-dependent manner. CONCLUSIONS PB inhibits proliferation via cyclin-dependent kinase and induces caspase-dependent apoptosis in HGC-27 cells, suggesting that PB might be a novel and effective agent for undifferentiated GC therapy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subtype of leukemia with poor prognosis, and biomarkers and novel therapeutic targets are urgently needed for this disease. Our previous studies have found that inhibition of the B-cell leukemia/lymphoma 11B (BCL11B) gene could significantly promote the apoptosis and growth retardation of T-ALL cells, but the molecular mechanism underlying this effect remains unclear. This study intends to investigate genes downstream of BCL11B and further explore its function in T-ALL cells. We found that PTK7 was a potential downstream target of BCL11B in T-ALL. Compared with the healthy individuals (HIs), PTK7 was overexpressed in T-ALL cells, and BCL11B expression was positively correlated with PTK7 expression. Importantly, BCL11B knockdown reduced PTK7 expression in T-ALL cells. Similar to the effects of BCL11B silencing, downregulation of PTK7 inhibited cell proliferation and induced apoptosis in Molt-4 cells via up-regulating the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p27. Altogether, our studies suggest that PTK7 is a potential downstream target of BCL11B, and downregulation of PTK7 expression via inhibition of the BCL11B pathway induces growth retardation and apoptosis in T-ALL cells.

Additional file 1. Materials and Methods.

Additional file 2: Figure S1. Expression patterns of BCL11B and PTK7 in the GSE28497 dataset. High expression of BCL11B (A) and PTK7 (B) in T-ALL. (C) BCL11B and PTK7 had a positive correlation.

Study of the molecular mechanisms underlying cancer immune escape is one of the core issues in immuno-oncology research. Cancer cells can evade T cell cytotoxicity by exploiting the upregulation of T cell inhibitory receptors on T cells and their ligands on cancer cells. These upregulated proteins include the inhibitory receptor programmed cell-death protein 1 (PD-1) and its ligand programmed cell death 1 ligand 1 (PD-L1), which can induce T cell exhaustion and reduce T cell activation. Characterizing PD-1 regulation will help to elucidate the molecular mechanisms underlying T cell exhaustion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-1 during gene transcription, post-transcriptional regulation, and post-translational modification and influence the effects of the anticancer immune response by targeting PD-1. In this review,we summarize the mechanisms of PD-1 regulation in T cells.

Chronic myeloid leukemia (CML) is a clonal disease characterized by the presence of the constitutively active tyrosine kinase BCR-ABL oncoprotein. Although BCR-ABL is crucially important for pathogenesis and treatment response, it is thought that some additional factors might be involved in the regulation of these processes. Aberrant expression of long noncoding RNAs (lncRNAs) has recently been identified to be involved in various diseases including cancer, suggesting that lncRNAs may play a role in BCR-ABL-mediated CML. In this study, we found that nuclear-enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in primary CML cells. NEAT1 expression could be restored by inhibiting BCR-ABL expression or its kinase activity in K562 cells. We also demonstrated that NEAT1 is regulated by c-Myc. Knockdown of NEAT1 could promote imatinib (IM)-induced apoptosis, and we demonstrated that the NEAT1-binding paraspeckle protein splicing factor proline/glutamine-rich (SFPQ) is required for NEAT1-mediated apoptosis in K562 cells. RNA-seq analysis revealed that SFPQ regulates cell growth and death pathway-related genes, confirming its function in IM-induced apoptosis. Collectively, these results assign a biological function to the NEAT1 lncRNA in CML apoptosis and may lead to fuller understanding of the molecular events leading to CML. Electronic supplementary material The online version of this article (10.1186/s12943-018-0884-z) contains supplementary material, which is available to authorized users.

Chronic myeloid leukemia (CML) is associated with chromosomal translocation t(9; 22), which results in formation of the BCR-ABL oncogene. CML is treated with tyrosine kinase inhibitors (TKIs), which target BCR-ABL, to eradicate BCR-ABL + cells. However, the TKI imatinib (IM) fails to eliminate quiescent leukemia stem cells (LSCs) in CML. In this study, we demonstrate that transcription factor TAL1 is down-regulated in CML LSCs by BCR-ABL, and IM triggers TAL1 mRNA expression. In addition, loss of TAL1 abrogates IM-induced CML cell apoptosis. RNA-seq analysis suggests that TAL1 expression may affect PI3K/AKT pathway. Moreover, depletion of TAL1 inhibits the expression of PTEN, which is a negative regulator of the PI3K/AKT pathway. Our results reveal an unexpected involvement of TAL1 in CML etiology and demonstrate that TAL1 may regulate PTEN expression and lead to inhibition of the PI3K/AKT pathway in the response of CML cells to TKI. These results implicate regulation of PTEN expression as a novel mechanism for the transcriptional regulatory networks of TAL1 in CML.

Epstein-Barr virus (EBV) is a human cancer-related virus closely associated with lymphoid and epithelial malignancies, and EBV glycoprotein B (gB) plays an essential role in viral entry into both B cells and epithelial cells by promoting cell-cell fusion. EBV gB is exclusively modified with high-mannose-linked N-glycans and primarily localizes to the endoplasmic reticulum (ER) with low levels on the plasma membrane (PM). However, the mechanism through which gB is regulated within host cells is largely unknown. Here, we report the identification of F-box only protein 2 (FBXO2), an SCF ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans and attenuates EBV infectivity by targeting N-glycosylated gB for degradation. gB possesses seven N-glycosylation sites, and FBXO2 directly binds to these high-mannose moieties through its sugar-binding domain. The interaction promotes the degradation of glycosylated gB via the ubiquitin-proteasome pathway. Depletion of FBXO2 not only stabilizes gB but also promotes its transport from the ER to the PM, resulting in enhanced membrane fusion and viral entry. FBXO2 is expressed in epithelial cells but not B cells, and EBV infection up-regulates FBXO2 levels. In summary, our findings highlight the significance of high-mannose modification of gB and reveal a novel host defense mechanism involving glycoprotein homeostasis regulation., Author summary EBV envelope glycoprotein B (gB) is a core component of the fusion machinery and plays an essential role in viral entry. EBV gB has been characterized as a high-mannose-containing glycoprotein, but the significance of this sugar type is unknown. In this work, we report the identification of FBXO2, a glycosylation-dependent E3 ubiquitin ligase component recognizing N-linked high-mannose oligosaccharides, as a novel gB-interacting host protein that controls the levels of gB glycosylation and its membrane transport. The homogenous high-mannose type N-glycan structure as a “script” that directs the degradation of the glycosylated gB by SCFFBXO2 E3 ubiquitin ligase. Our results propose a novel host defense mechanism by which host cells sense the penetrated EBV and attenuate the infectivity of progeny virus.

Figure S1. Analysis of lncRNA expression. Figure S2. Imatinib-induced NEAT1 is associated with c-Myc. Figure S3. Effects of NEAT1 on apoptosis in K562 cells. (DOCX 524 kb)

Materials and methods. (DOCX 19 kb)

Purpose To evaluate in vivo features of Schlemm's canal (SC) in patients with primary open-angle glaucoma (POAG) with spectral-domain optical coherence tomography (SD-OCT) and to investigate the relationship of SC size with intraocular pressure (IOP) and glaucoma severity. Design Prospective, comparative study. Participants Fifty Chinese patients with newly diagnosed POAG who had not undergone surgery and 50 normal Chinese subjects from a population-based, cross-sectional study in Shanghai. Methods All participants underwent SD-OCT. The diameter and area of SC were examined in the temporal and nasal sections and measured with customized software. Main Outcome Measures Patient demographics, repeatability and reproducibility assessed with the coefficient of variation (CV) and the intraclass correlation coefficient (ICC), SC parameters and their correlation with IOP, and the mean deviation (MD) of the visual field were analyzed. Results The percentage of sections in which SC was observable was similar between eyes with POAG and normal eyes, and ranged from 78% to 86%. For intraobserver repeatability, the CV and ICC values were 7.9% and 0.97 for diameter, and 13.8% and 0.83 for area, respectively. For interobserver repeatability, the CV and ICC values were 13.6% and 0.89 for diameter, and 13.4% and 0.80 for area, respectively. Significant differences between the 2 groups were found for the average SC area (11332±2015 μm 2 vs. 13991±1357 μm 2 ; P P = 0.195). In addition, the mean IOP values correlated well only with the SC area (ρ = −0.674, P P = 248). No significant correlations were found between the MD values and the SC parameters. Conclusions Eyes with POAG have a decreased SC area compared with normal eyes. A correlation between the SC area and the IOP also was observed. However, the degree of glaucoma damage was not consistently associated with the SC area. Spectral-domain OCT could be used for investigating SC changes in patients with glaucoma. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Background Acute promyelocytic leukemia (APL) is associated with chromosomal translocation t(15;17), which results in the proliferation of morphologically abnormal promyelocytes. Gain of supernumerary copies of the 8q24 chromosomal region, which harbors MYC and PVT1, has been shown to be the most common secondary alteration in human APL. Increased MYC can accelerate the development of myeloid leukemia in APL. However, the role that the expression of the long non-coding RNA (lncRNA) PVT1 plays in the pathogenesis of APL remains largely unknown. Findings In this study, we first analyzed the lncRNA PVT1 expression level in peripheral blood cells from 28 patients with de novo APL, and significantly upregulated PVT1 was found in APL patients compared with healthy donors. We then observed significantly lower MYC and PVT1 expression during all-trans retinoic acid (ATRA)-induced differentiation and cell cycle arrest in the APL cell line. MYC knockdown in NB4 cells led to PVT1 downregulation. Moreover, PVT1 knockdown by RNA interference led to suppression of the MYC protein level, and cell proliferation was inhibited. Conclusion Our findings reveal that the lncRNA PVT1 may play an important role in the proliferation of APL cells and may be useful for future therapeutic management. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0223-4) contains supplementary material, which is available to authorized users.

Previous analyses have reported that the human monocytic cell line THP1 can be differentiated into cells with macrophage-like characteristics by phorbol 12-myristate 13-acetate (PMA). However, little is known about the mechanism responsible for regulating this differentiation process. Here, we performed high-throughput RNA-Seq analysis to investigate the genes differently expressed in THP1 cells treated with and without PMA and examined those that may be responsible for the PMA-induced differentiation of monocytes into macrophages. We found 3,000 genes to be differentially expressed after PMA treatment. Gene ontology analysis revealed that genes related to cellular processes and regulation of biological processes were significantly enriched. KEGG analysis also demonstrated that the differentially expressed genes (DEGs) were significantly enriched in the PI3K/AKT signaling pathway and phagosome pathway. Importantly, we reveal an important role of the PI3K/AKT pathway in PMA-induced THP1 cell differentiation. The identified DEGs and pathways may facilitate further study of the detailed molecular mechanisms of THP1 differentiation. Thus, our results provide numerous potential therapeutic targets for modulation of the differentiation of this disease.

Background Acute promyelocytic leukemia (APL) is characterized by the reciprocal translocation t(15;17), which fuses PML with retinoic acid receptor alpha (RARα). Although PML-RARα is crucially important for pathogenesis and responsiveness to treatment, the molecular and cellular mechanisms by which PML-RARα exerts its oncogenic potential have not been fully elucidated. Recent reports have suggested that long non-coding RNAs (lncRNAs) contribute to the precise control of gene expression and are involved in human diseases. Little is known about the role of lncRNA in APL. Methods We analyzed NEAT1 expression in APL samples and cell lines by real-time quantitative reverse transcription-PCR (qRT-PCR). The expression of PML-RARα was measured by Western blot. Cell differentiation was assessed by measuring the surface CD11b antigen expression by flow cytometry analysis. Results We found that nuclear enriched abundant transcript 1 (NEAT1), a lncRNA essential for the formation of nuclear body paraspeckles, is significantly repressed in de novo APL samples compared with those of healthy donors. We further provide evidence that NEAT1 expression was repressed by PML-RARα. Furthermore, significant NEAT1 upregulation was observed during all-trans retinoic acid (ATRA)-induced NB4 cell differentiation. Finally, we demonstrate the importance of NEAT1 in myeloid differentiation. We show that reduction of NEAT1 by small interfering RNA (siRNA) blocks ATRA-induced differentiation. Conclusions Our results indicate that reduced expression of the nuclear long noncoding RNA NEAT1 may play a role in the myeloid differentiation of APL cells. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-693) contains supplementary material, which is available to authorized users.