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1.
Am J Hematol ; 98(11): 1742-1750, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37647123

ABSTRACT

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

2.
Cancer Biol Ther ; 23(1): 369-377, 2022 12 31.
Article in English | MEDLINE | ID: mdl-35491899

ABSTRACT

Glioma-associated oncogene (Gli) antagonist-61 (GANT61) not only suppresses the malignant behavior of several cancers but also presents synergistic effects with other anticancer agents on suppressing the progression of cancers, while relevant information is rare in anaplastic thyroid carcinoma (ATC). This study aimed to explore the therapeutic effect of GANT61 in ATC and its molecular mechanism. ATC cells (8505C and CAL-62) were treated with GANT61, followed by detection of cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) markers. Subsequently, RNA sequencing was performed to explore the potential downstream pathway. Following that, rescue experiments were conducted by SC79 (AKT activator) or colivelin (STAT3 activator) monotreatment or combined with GANT61 in ATC cells. GANT61 reduced Gli1 expression, suppressed proliferation at several time settings, promoted apoptosis, inhibited invasion and increased E-cadherin while decreased Vimentin and Snail expressions (EMT markers) in ATC cells. The subsequent RNA sequence identified 85 upregulated differentially expressed genes (DEGs) and 71 downregulated DEGs in GANT61-treated ATC cells, which were mainly enriched in PI3K/AKT, JAK/STAT, Hedgehog and mTOR pathways. Next, the inactivation of AKT/mTOR and JAK/STAT3 pathways by GANT61 treatment was verified by western blot. The following rescue experiments showed that SC79 or colivelin treatment promoted the malignant behaviors of ATC cells. More importantly, SC79 or colivelin treatment compensated the effect of GANT61 treatment on cell proliferation at several time settings and apoptosis, invasion, and part of that on EMT in ATC cells. GANT61 suppresses cell survival, invasion and EMT through inactivating AKT/mTOR or JAK/STAT3 pathways in ATC.


Subject(s)
Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Cell Line, Tumor , Cell Movement , Cell Survival , Epithelial-Mesenchymal Transition/genetics , Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pyridines , Pyrimidines , STAT3 Transcription Factor/metabolism , TOR Serine-Threonine Kinases/metabolism , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/genetics , Thyroid Neoplasms/pathology
3.
Am J Transl Res ; 13(11): 12302-12317, 2021.
Article in English | MEDLINE | ID: mdl-34956454

ABSTRACT

OBJECTIVE: MicroRNAs (miRNAs) play a big role in the regulation of non-small cell lung cancer (NSCLC) development. The objective of this study is to determine how DNA methylation regulates miR-433 in NSCLC. METHODS: The degree of DNA methylation was determined, and the relevance of miR-433 and the features of NSCLC patients were assessed. The MiR-433 and CREB1 expressions were tested, and the biological characteristics of the NSCLC cells were determined. Subcutaneous tumorigenesis in nude mice and luciferase activity assays were performed. RESULTS: MiR-433 was downregulated, and CREB1 was upregulated in the NSCLC tissues, and the methylating rate of the C-phosphate-G (CpG) island in the miR-433 promoter region was enhanced. MiR-433 was also downregulated, and CREB1 was upregulated in the NSCLC cells and there was a low degree of promoter methylation of miR-433 in the NSCLC cells after demethylation. Upregulated miR-433 or downregulated CREB1 repressed the cell vitality and colony formation abilities and increased the amount of apoptotic A549 cells. Moreover, upregulated miR-433 also decelerated tumor growth. Conversely, the H460 cells and xenografts with reduced miR-433 or overexpressed CREB1 had contrary results. CREB1 was found to be targeted by miR-433, as verified by a luciferase activity assay. CONCLUSION: We found that DNA methylation can downregulate miR-433 in NSCLC, which promotes the malignant behaviors of NSCLC cells.

4.
Front Oncol ; 11: 608238, 2021.
Article in English | MEDLINE | ID: mdl-34195068

ABSTRACT

Recent studies have demonstrated the benefits of metformin on patients with lymphomas. B-cell receptor (BCR)-PI3K-AKT pathway-dependent cholesterol synthesis may represent a positive feedback mechanism responsible for the pathogenesis of BCR-dependent diffuse large B-cell lymphomas (DLBCLs). Thus, restriction of lipid synthesis would affect the integrity of lipid-forming membranes and block the BCR signaling pathway. Our in vitro findings suggested that the blocking effect of metformin on BCR signaling pathway is possibly exerted via blocking the biosynthesis of cholesterol. A retrospective case-control study was subsequently conducted on type II diabetic patients with DLBCL who were on metformin. Metformin was identified to be associated with improved response rate and PFS in diabetic patients and appeared to be an effective therapeutic drug against DLBCL.

5.
Blood Adv ; 5(1): 185-197, 2021 01 12.
Article in English | MEDLINE | ID: mdl-33570628

ABSTRACT

Inhibition of the B-cell receptor (BCR) signaling pathway is highly effective in B-cell neoplasia through Bruton tyrosine kinase inhibition by ibrutinib. Ibrutinib also disrupts cell adhesion between a tumor and its microenvironment. However, it is largely unknown how BCR signaling is linked to cell adhesion. We observed that intrinsic sensitivities of mantle cell lymphoma (MCL) cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion signatures were simultaneously downregulated by ibrutinib in the ibrutinib-sensitive, but not ibrutinib-resistant, cells. Among the differentially expressed genes, RAC2, part of the BCR signature and a known regulator of cell adhesion, was downregulated at both the RNA and protein levels by ibrutinib only in sensitive cells. RAC2 physically associated with B-cell linker protein (BLNK), a BCR adaptor molecule, uniquely in sensitive cells. RAC2 reduction using RNA interference and CRISPR impaired cell adhesion, whereas RAC2 overexpression reversed ibrutinib-induced cell adhesion impairment. In a xenograft mouse model, mice treated with ibrutinib exhibited slower tumor growth, with reduced RAC2 expression in tissue. Finally, RAC2 was expressed in ∼65% of human primary MCL tumors, and RAC2 suppression by ibrutinib resulted in cell adhesion impairment. These findings, made with cell lines, a xenograft model, and human primary lymphoma tumors, uncover a novel link between BCR signaling and cell adhesion. This study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and drug development.


Subject(s)
Lymphoma, Mantle-Cell , Animals , Cell Adhesion , Drug Resistance, Neoplasm , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/genetics , Mice , Receptors, Antigen, B-Cell , Signal Transduction , Tumor Microenvironment
6.
Front Oncol ; 10: 803, 2020.
Article in English | MEDLINE | ID: mdl-32582543

ABSTRACT

The well-established cell-of-origin (COO) algorithm categorizes diffuse large B-cell lymphoma (DLBCL) into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subgroups through gene expression profiling. We aimed to develop and validate a qPCR-based gene expression assay to determine the COO subgroups of DLBCL with formalin-fixed paraffin-embedded (FFPE) tissue. We first established a DLBCL transcriptome database of 1,016 samples retrieved from three published datasets (GSE10846, GSE22470, and GSE31312). With this database, we identified a qPCR-based 32-gene expression signature (DLBCL-COO assay) that is significantly associated with the COO subgroups. The DLBCL-COO assay was further validated in a cohort of 160 Chinese DLBCL patients. Biopsy samples from DLBCL patients with paired FFPE and fresh frozen tissue were collected to assign COO subtypes based on the immunohistochemistry (IHC) algorithm (Han's algorithm), DLBCL-COO assay, and global gene expression profiling with RNA-seq. For 111 paired FFPE and fresh DLBCL samples, the concordance between the IHC, qPCR, and RNA-seq methods was 77.5% and 91.9%, respectively. The DLBCL-COO assay demonstrated a significantly superior concordance of COO determination with the "gold standard" RNA-seq compared with the IHC assignment with Han's algorithm (P = 0.005). Furthermore, the overall survival of GCB patients defined by the DLBCL-COO assay was significantly superior to that of ABC patients (P = 0.023). This effect was not seen when the tumors were classified by the IHC algorithm. The DLBCL-COO assay provides flexibility and accuracy in DLBCL subtype characterization. These findings demonstrated that the DLBCL-COO assay might serve as a useful tool for guiding prognostic and therapeutic options for DLBCL patients.

7.
Leuk Lymphoma ; 61(6): 1364-1371, 2020 06.
Article in English | MEDLINE | ID: mdl-32090646

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive lymphomas exhibiting increased glucose uptake. However, some DLBCLs featuring relatively low 18F-fluorodeoxyglucose (18F-FDG) uptake denoted by the maximum standardized uptake value (SUVmax) on PET/CT have been identified. The biologic correlates of such a heterogeneity have remained largely unknown. Herein, we immunohistochemically detected and found low FDG-avid DLBCL cases featuring lower expression of some key molecules involved in B-cell receptor (BCR) signaling (pSYK) and glucose metabolism (GLUT1 and HK2). Besides, BCR-deficient DLBCL xenografts were found displaying lower SUVmax and expressions of pSYK, GLUT1, and HK2. Further immunoblotting demonstrated expressions of GLUT1 and HK2 in BCR-dependent DLBCLs could be down-regulated by a chemical SYK inhibition, whereas the inhibitory effects were not observed in BCR-deficient tumors. These findings suggest low FDG-avid DLBCLs display a silent BCR signaling and PET/CT might be utilized to tailor the BCR signaling-inhibitory treatment.


Subject(s)
Fluorodeoxyglucose F18 , Lymphoma, Large B-Cell, Diffuse , Humans , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/genetics , Positron Emission Tomography Computed Tomography , Receptors, Antigen, B-Cell , Signal Transduction
8.
Lab Invest ; 99(10): 1418-1427, 2019 10.
Article in English | MEDLINE | ID: mdl-31197205

ABSTRACT

Targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway represents a milestone in cancer therapy. However, the biologic features of diffuse large B-cell lymphoma (DLBCL) with PD-L1 expression remains unknown. We evaluated the correlation between pSYK and PD-L1 mRNA levels with RNAscope in situ hybridization and protein levels with immunohistochemistry in 108 cases of DLBCL, 25 of which featured loss of B-cell receptor (BCR), and investigated the effects of BCR signaling and MYC on PD-L1 mRNA and protein level with qPCR, immunoblotting and flow cytometery in DLBCL cell lines. PD-L1 amplification was detected with fluorescent in situ hybridization. Animal studies were applied to validate the in vitro findings. pSYK and MYC correlated with both PD-L1 mRNA and protein level. Genetic aberrations involving PD-L1 were rare in DLBCL. BCR signaling and MYC increased PD-L1 mRNA and protein expression. Inhibition of BCR signaling and BCR knockdown down-regulated PD-L1. DLBCL with a loss of loss of BCR showed low levels of PD-L1 mRNA and protein. PD-L1 was down-regulated by ibrutinib in a xenograft mouse model and correlated with slower tumor growth. In conclusion, this study demonstrates that DLBCL with PD-L1 expression features an activated B-cell receptor signal pathway, and that BCR inhibition and PD-L1 blockage may potentially synergize to targeting DLBCL.


Subject(s)
B7-H1 Antigen/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Receptors, Antigen, B-Cell/metabolism , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Animals , Female , Humans , Male , Mice, SCID , Middle Aged , Piperidines , Pyrazoles , Pyrimidines , Retrospective Studies , Signal Transduction , Syk Kinase/metabolism , Young Adult
9.
Histopathology ; 74(4): 618-628, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30286249

ABSTRACT

AIMS: The protein expression of programmed death-ligand 1 (PD-L1) has been recognised as being a biomarker for poor prognosis in diffuse large B-cell lymphoma (DLBCL). The aims of this study were to determine PD-L1 DNA status and mRNA status, and to explore whether they contribute to protein expression and their clinicopathological correlation in DLBCL. METHODS AND RESULTS: In this study, we used fluorescence in-situ hybridisation, RNA in-situ hybridisation and immunohistochemistry to determine PD-L1 status at three different levels in 287 DLBCL samples with follow-up. Their correlation and clinical pathological relevance were also analysed. Our results showed that 1.7% (3/175) of patients had PD-L1 DNA amplification, 19.9% (57/287) had high PD-L1 mRNA expression, and 11.8% (34/287) had high PD-L1 protein expression. Both mRNA and protein expression of PD-L1 were significantly higher in non-germinal centre B-cell-like (GCB) DLBCL than in GCB DLBCL (P < 0.05). In addition, the patients with high PD-L1 mRNA or high PD-L1 protein expression but no PD-L1 DNA amplification had significantly poorer overall survival (OS) than those with low PD-L1 expression (P < 0.05). Furthermore, we found that PD-L1 mRNA and PD-L1 protein expression were highly correlated (P = 0.012), which was observed in all three samples with DNA amplification. CONCLUSIONS: PD-L1 DNA amplification is a rare event, PD-L1 mRNA is the main contributor to the high PD-L1 protein expression, and the latter two will serve as important biomarkers for predicting the prognosis of DLBCL patients and selecting them for immunotherapy.


Subject(s)
B7-H1 Antigen/biosynthesis , Biomarkers, Tumor/analysis , Lymphoma, Large B-Cell, Diffuse/pathology , Adolescent , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/analysis , DNA/analysis , Female , Gene Amplification , Humans , Male , Middle Aged , RNA, Messenger/analysis , Young Adult
10.
Mol Cancer Ther ; 17(12): 2564-2574, 2018 12.
Article in English | MEDLINE | ID: mdl-30510142

ABSTRACT

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFκB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFκB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IκB that was accompanied by the reduction of DNA-binding activity of NFκB, suggesting that NFκB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFκB and IκB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFκB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFκB inhibition.


Subject(s)
Cell Nucleus/metabolism , Drug Resistance, Neoplasm , Hydrazines/therapeutic use , I-kappa B Proteins/metabolism , Karyopherins/antagonists & inhibitors , Lymphoma, Mantle-Cell/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Triazoles/therapeutic use , Adenine/analogs & derivatives , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Hydrazines/pharmacology , Karyopherins/metabolism , NF-kappa B/metabolism , Piperidines , Protein Subunits/metabolism , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptors, Cytoplasmic and Nuclear/metabolism , Triazoles/pharmacology , Exportin 1 Protein
11.
Pathology ; 50(7): 725-729, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30389217

ABSTRACT

Programmed cell death ligand 1 (PD-L1) is upregulated in various types of haematological malignancies and is associated with immunosuppression. This study aimed to investigate the expression pattern of PD-L1 in Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). We retrospectively analysed clinicopathological characteristics in 30 cases of EBV-positive DLBCL and immunohistochemically evaluated the level of membrane bound PD-L1 protein. Twenty-eight cases expressed PD-L1 protein, 15 of which showed an intense positive staining. In addition, we investigated the relationships between PD-L1 protein and PD-L1 mRNA and MYC, respectively. The expression level of PD-L1 protein was not fully parallel with PD-L1 mRNA, and no significant correlation was observed between PD-L1 protein and MYC. Notably, PD-L1 mRNA was at a low dosage, which indicated that there might be other mechanisms inducing the overexpression of membrane bound PD-L1 protein apart from genetic alterations. Furthermore, the low expression level of MYC may not interfere with the PD-L1 protein expression in EBV-positive DLBCL. In conclusion, overexpression of PD-L1 protein can be observed in EBV-positive DLBCL, and the level was non-parallel with both PD-L1 mRNA and MYC. Moreover, we emphasise that immunohistochemistry is a clinically reasonable method for screening formalin fixed, paraffin embedded (FFPE) tumour samples in this entity.


Subject(s)
B7-H1 Antigen/metabolism , Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human/isolation & purification , Lymphoma, Large B-Cell, Diffuse/pathology , Proto-Oncogene Proteins c-myc/metabolism , Adult , Aged , Aged, 80 and over , B7-H1 Antigen/genetics , Cell Membrane/metabolism , Epstein-Barr Virus Infections/metabolism , Epstein-Barr Virus Infections/virology , Female , Herpesvirus 4, Human/genetics , Humans , Immunohistochemistry , In Situ Hybridization , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/virology , Male , Middle Aged , Phenotype , Proto-Oncogene Proteins c-myc/genetics , RNA, Messenger/genetics , Retrospective Studies , Young Adult
13.
J Pathol ; 246(2): 141-153, 2018 10.
Article in English | MEDLINE | ID: mdl-29876933

ABSTRACT

Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers; however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, the interaction between HDAC6 and HR23B downregulated HR23B expression, thereby reducing the levels of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase for hepatocyte growth factor receptor (MET), which resulted in the inhibition of MET ubiquitination-dependent degradation. In addition, enhanced HDAC6 expression and decreased HR23B expression were correlated with poor overall survival rates among patients with DLBCL. Taken together, these results establish an HDAC6-HR23B-MET axis and indicate that HDAC6 is a potent promoter of lymphomagenesis in DLBCL. Thus, a therapeutic strategy based on HDAC6 inhibitors in combination with MET inhibitors is promising. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Crizotinib/pharmacology , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Repair Enzymes/metabolism , DNA-Binding Proteins/metabolism , Drug Synergism , Female , Histone Deacetylase 6/genetics , Histone Deacetylase 6/metabolism , Humans , Lymphoma, Large B-Cell, Diffuse/enzymology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Proteolysis , Proto-Oncogene Proteins c-cbl/metabolism , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Signal Transduction/drug effects , Tumor Burden/drug effects , Ubiquitination , Xenograft Model Antitumor Assays
14.
Ann Diagn Pathol ; 34: 155-160, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29660568

ABSTRACT

To investigate the clinicopathologic features and differential diagnoses of interdigitating dendritic cell sarcoma (IDCS), the clinical, morphological and immunohistochemical features of eight cases of IDCS were collected and analyzed. Three patients were males and five were females, the mean age and the median age were 56.5 years and 57 years respectively. Clinically, the majority of cases involved lymph nodes. Microscopically, neoplastic cells were spindle or ovoid, forming fascicles or whorls. Every case had active mitosis figures. Immunohistochemically, these neoplastic cells were consistently positive for S100, but negative for CD21 and specific B-cell and T-cell associated antigens. Follow-up results were available in 7 cases, of which 5 cases of localized lesions survived, 2 cases died of organ involvement. Interdigitating dendritic cell sarcoma is an extremely rare neoplasm, with inferior prognosis and without standard treatment regimen. IDCS has similar but unique clinicopathologic features and the differential diagnoses include other histiocytic and dendritic cell neoplasms and malignant melanoma.


Subject(s)
Dendritic Cell Sarcoma, Interdigitating/diagnosis , Adult , Aged , Dendritic Cell Sarcoma, Interdigitating/pathology , Diagnosis, Differential , Female , Humans , Immunohistochemistry , Lymph Nodes/pathology , Male , Middle Aged , Prognosis
15.
Oncotarget ; 9(3): 3956-3967, 2018 Jan 09.
Article in English | MEDLINE | ID: mdl-29423097

ABSTRACT

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma with limited data. In this study, a population-based study of primary breast DLBCL in the United States was performed to determine its incidence trends, prognostic factors, survival, the role of surgery as well as the comparison with nodal DLBCL. 1021 patients diagnosed with breast DLBCL were identified in the Surveillance, Epidemiology, and End Results (SEER) cancer registries from 1973-2014. The incidence of both breast and nodal DLBCL increased over time. Patients with breast DLBCL were older, mainly women, diagnosed at earlier stages and had lower prevalence in white and black races compared with nodal DLBCL. Multivariate analysis revealed older age (≥ 70 years old) and advanced stage as independent predictors of worse OS. Independent predictor of better DSS were younger age (< 70 years old), early stage and diagnosis after 2000. When analyzed according to age, stage, race, tumor laterality and year of diagnosis, the overall survival did not benefit from surgery except in patients diagnosed between 2001-2010 and the surgery rate decreased overtime. Compared with nodal DLBCL, breast DLBCL patients exhibited a better outcome. In conclusion, breast DLBCL is a rare tumor with increasing incidence and improved survival over the last four decades. The introduction of rituximab seems to improve the outcome of breast DLBCL. Further studies are needed to advance our understanding of breast DLBCL and optimize the treatment strategy.

16.
Blood ; 131(12): 1325-1336, 2018 03 22.
Article in English | MEDLINE | ID: mdl-29437589

ABSTRACT

B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of their propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B-cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here, we identify prolyl 4-hydroxylase 2 (P4HA2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/extracellular signal-regulated kinase pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but upregulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Biomarkers, Tumor/metabolism , Cell Proliferation , Lymphoma, Large B-Cell, Diffuse/metabolism , MAP Kinase Signaling System , Neoplasm Proteins/metabolism , Prolyl Hydroxylases/metabolism , Adaptor Proteins, Signal Transducing/genetics , Biomarkers, Tumor/genetics , Cell Line, Tumor , GTPase-Activating Proteins , Humans , Hydroxylation , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Neoplasm Proteins/genetics , Prolyl Hydroxylases/genetics , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Proteolysis
17.
PLoS One ; 12(6): e0178416, 2017.
Article in English | MEDLINE | ID: mdl-28665943

ABSTRACT

We retrospectively analysed 17 cases of anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+, LBCL) according to the morphological, immunohistochemical, molecular and clinical features, using which we intend to elucidate the clinicopathological characteristics of this rare entity. In this study, all cases de facto share common features that defined them as a single entity, and various characteristics may expand the spectrum. Among 15 cases, 60% followed an aggressive clinical course with advanced stage and high IPI scores; the median survival of these patients was only 8 months. An analysis showed that both the IPI score and the Ann Arbor stage were significant prognostic factors. Most patients received a chemotherapy regimen including CHOP, CHOEP, EPOCH, and CVAD, and some also underwent localized radiotherapy. However, ALK+, LBCL cases display a dismal clinical outcome and can only be cured with conventional chemotherapy protocols at the stage of localized disease. Novel front-line intensive chemotherapy regimens should therefore be evaluated in this group of patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/pathology , Receptor Protein-Tyrosine Kinases/metabolism , Adult , Aged , Anaplastic Lymphoma Kinase , Child , Female , Humans , In Situ Hybridization, Fluorescence , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/enzymology , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Middle Aged , Prognosis , Reverse Transcriptase Polymerase Chain Reaction , Young Adult
18.
Histopathology ; 71(5): 778-785, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28639315

ABSTRACT

AIMS: MYC overexpression is a common feature of diffuse large B-cell lymphoma (DLBCL) and is associated with poor prognosis in patients with this neoplasm. We aimed to investigate the underlying mechanisms of MYC dysregulation, as they have not been fully determined. METHODS AND RESULTS: We immunohistochemically evaluated the correlation between B-cell receptor (BCR)-phosphoinositide 3-kinase (PI3K) pathway activity and MYC level in 108 cases of de-novo DLBCL, 25 of which featured loss of BCR, and investigated the effects of BCR-PI3K signalling on MYC level and phosphorylation in DLBCL cell lines. The expression levels of phospho-SYK and phospho-AKT correlated with MYC expression in BCR-positive DLBCL. MYC expression was significantly lower in BCR-negative tumour tissues than in BCR-positive tumour tissues. Upon BCR stimulation, the BCR-positive cell lines showed active BCR-PI3K signalling and decreased MYC phosphorylation at T58, leading to an increased overall level of MYC. Conversely, inhibition of BCR-PI3K signalling increased MYC phosphorylation and thus resulted in a decreased overall level of MYC. No effects were observed in the BCR-negative cell lines. CONCLUSIONS: Overexpression of MYC in DLBCL can be driven by the BCR-PI3K signalling pathway via dephosphorylation at T58, and BCR inhibitors may exert their functions by down-regulation of MYC.


Subject(s)
Lymphoma, Large B-Cell, Diffuse/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-bcr/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Receptors, Antigen, B-Cell/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Lymphoma, Large B-Cell, Diffuse/metabolism , Male , Middle Aged , Retrospective Studies , Signal Transduction/physiology , Young Adult
19.
Onco Targets Ther ; 10: 2239-2247, 2017.
Article in English | MEDLINE | ID: mdl-28461758

ABSTRACT

PIK3CA has been extensively investigated from its molecular mechanism perspective and epidemiological association with its mutations in different types of cancers. However, little has been reported regarding the clinicopathological significance of PIK3CA expression in diffuse large B cell lymphoma (DLBCL). In the present study, we investigated the clinicopathological significance of PIK3CA in DLBCL by performing immunohistochemical evaluation of PIK3CA in tissue microarrays consisting of 199 cases of DLBCL. Kaplan-Meier survival analysis was performed to analyze the association between PIK3CA expression and overall prognosis. To further investigate the role of PIK3CA mediated in the proliferation, cell cycle and apoptosis of DLBCL cells, Cell Counting Kit-8 (CCK-8) and flow cytometry assays were carried out in DLBCL cell lines after successful, stable knockdown of PIK3CA using lentiviral short hairpin RNA inference. Our results indicated that although PIK3CA was shown to be extensively expressed in DLBCL, no significant association was observed between PIK3CA expression and clinical outcome or between PIK3CA expression and other clinicopathological parameters, except between performance state (PS) and phosphorylated AKT (p-AKT) expression. In vitro studies revealed that in DLBCL cell lines OCI-LY8 and OCI-LY1, knockdown of PIK3CA could significantly reduce proliferation and promote apoptosis in a G1-phase arrested manner. Additionally, p27 was shown to be markedly upregulated, whereas p-AKT and cyclin D1 were found to be pronouncedly downregulated after stable knockdown of PIK3CA. Together, our results support the oncogenic property of PIK3CA in DLBCL.

20.
Am J Surg Pathol ; 41(4): 541-549, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28291124

ABSTRACT

Components of the B-cell receptor (BCR) signaling pathway represent promising therapeutic targets in diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. MYC, a transcriptional factor and oncoprotein, is overexpressed in a fraction of DLBCL and indicates poor prognosis and aggressive clinical course when treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, BCR signaling status in MYC-positive DLBCL cases and the potential efficacy of BCR signal inhibitors in treating this aggressive disease are unknown. To further elucidate the BCR signaling pathway in MYC-positive DLBCL, we analyzed the levels of BCR-associated genes according to MYC gene status, detected phosphorylated protein with primary DLBCL samples, and estimated the patient survival with MYC expression. In addition, we manipulated MYC gene expression and tested its effects on BCR signaling in vitro. We found that CD19, SYK, and BLK were highly expressed in DLBCL with MYC gene overexpression. MYC-positive DLBCL had higher levels of pSYK and pBLK, but only pSYK level correlated with patient survival. The in vitro studies demonstrated that overexpression of the MYC gene augmented BCR signaling, whereas MYC gene knockdown attenuated BCR signaling. Thus, MYC protein-positive DLBCL features highly activated BCR signaling and may represent a potential candidate for BCR inhibitor therapy.


Subject(s)
B-Lymphocytes/metabolism , Biomarkers, Tumor/metabolism , Lymphocyte Activation , Lymphoma, Large B-Cell, Diffuse/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Receptors, Antigen, B-Cell/metabolism , Adult , Aged , Aged, 80 and over , Antigens, CD19/genetics , Antigens, CD19/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Cell Line, Tumor , Female , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Phosphorylation , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/immunology , RNA Interference , Receptors, Antigen, B-Cell/immunology , Risk Factors , Signal Transduction , Syk Kinase/genetics , Syk Kinase/metabolism , Time Factors , Transfection , Young Adult , src-Family Kinases/metabolism
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