Yuxuan Liu

All Publications

• Uridine Synthesis Is the Metabolic Vulnerability in Relapse-Associated B-ALL Cells with Active Pre-BCR Signaling Liu, Y., Jiang, H., Stuani, L., Sarno, J., Domizi, P., Merchant, M., Jedoui, D., Jager, A., Huang, M., Lacayo, N. J., Sakamoto, K. M., Ye, J., Davis, K. L. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186925

  View details for Web of Science ID 001159740307086

• Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia. Nature communications Sarno, J., Domizi, P., Liu, Y., Merchant, M., Pedersen, C. B., Jedoui, D., Jager, A., Nolan, G. P., Gaipa, G., Bendall, S. C., Bava, F., Davis, K. L. 2023; 14 (1): 2935

  Abstract

  Resistance to glucocorticoids (GC) is associated with an increased risk of relapse in B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). Performing transcriptomic and single-cell proteomic studies in healthy B-cell progenitors, we herein identify coordination between the glucocorticoid receptor pathway with B-cell developmental pathways. Healthy pro-B cells most highly express the glucocorticoid receptor, and this developmental expression is conserved in primary BCP-ALL cells from patients at diagnosis and relapse. In-vitro and in vivo glucocorticoid treatment of primary BCP-ALL cells demonstrate that the interplay between B-cell development and the glucocorticoid pathways is crucial for GC resistance in leukemic cells. Gene set enrichment analysis in BCP-ALL cell lines surviving GC treatment show enrichment of B cell receptor signaling pathways. In addition, primary BCP-ALL cells surviving GC treatment in vitro and in vivo demonstrate a late pre-B cell phenotype with activation of PI3K/mTOR and CREB signaling. Dasatinib, a multi-kinase inhibitor, most effectively targets this active signaling in GC-resistant cells, and when combined with glucocorticoids, results in increased cell death in vitro and decreased leukemic burden and prolonged survival in an in vivo xenograft model. Targeting the active signaling through the addition of dasatinib may represent a therapeutic approach to overcome GC resistance in BCP-ALL.

  View details for DOI 10.1038/s41467-023-38456-y

  View details for PubMedID 37217509

• Single-cell technologies uncover intra-tumor heterogeneity in childhood cancers. Seminars in immunopathology Lo, Y., Liu, Y., Kammersgaard, M., Koladiya, A., Keyes, T. J., Davis, K. L. 2023

  Abstract

  Childhood cancer is the second leading cause of death in children aged 1 to 14. Although survival rates have vastly improved over the past 40years, cancer resistance and relapse remain a significant challenge. Advances in single-cell technologies enable dissection of tumors to unprecedented resolution. This facilitates unraveling the heterogeneity of childhood cancers to identify cell subtypes that are prone to treatment resistance. The rapid accumulation of single-cell data from different modalities necessitates the development of novel computational approaches for processing, visualizing, and analyzing single-cell data. Here, we review single-cell approaches utilized or under development in the context of childhood cancers. We review computational methods for analyzing single-cell data and discuss best practices for their application. Finally, we review the impact of several studies of childhood tumors analyzed with these approaches and future directions to implement single-cell studies into translational cancer research in pediatric oncology.

  View details for DOI 10.1007/s00281-022-00981-1

  View details for PubMedID 36625902

• NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proceedings of the National Academy of Sciences of the United States of America Liu, Y., Mondello, P., Erazo, T., Tannan, N. B., Asgari, Z., de Stanchina, E., Nanjangud, G., Seshan, V. E., Wang, S., Wendel, H. G., Younes, A. 2018; 115 (47): 12034-12039

  Abstract

  Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.

  View details for DOI 10.1073/pnas.1806928115

  View details for PubMedID 30404918

  View details for PubMedCentralID PMC6255185

• Prior Knowledge Integration Improves Relapse Prediction and Identifies Relapse Associated Mechanisms in Childhood B Cell Acute Lymphoblastic Leukemia Koladiya, A., Jager, A., Culos, A., Merchant, M., Liu, Y., Stuani, L., Sarno, J., Domizi, P., Mullighan, C. G., Aghaeepour, N., Bendall, S., Davis, K. L. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187264

  View details for Web of Science ID 001159306706074

• Enrichment in Metabolic Pathway Activation Corresponds to Immunoglobulin Gene Diversity across B Cell Developmental Stages in B-Lymphoblastic Leukemia Simpson, C., Liu, Y., Stuani, L., Jager, A., Baker, C., Adlowitz, D. G., Rock, P. J., Burack, R., Davis, K. L. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-189313

  View details for Web of Science ID 001159740302081

• Single-Cell Proteomic Analysis Defines Metabolic Heterogeneity in Response to Venetoclax in AML Stuani, L., Jager, A., Sahal, A., Koladiya, A., Sarno, J., Domizi, P., Liu, Y., De Mas, V., Recher, C., Vergez, F., Sarry, J., Davis, K. L. AMER SOC HEMATOLOGY. 2022: 1028-1029

  View details for DOI 10.1182/blood-2022-171009

  View details for Web of Science ID 000893223201014

• First-in-Class Histone Acetyltransferase (HAT) Activator, YF2, Modulates Immune Evasion in DLBCL, Enhancing the Effects of Immune Checkpoint Blockade Estrella, B., Pazos, M. A., Ricker, E. C., Ryu, Y., Piorczynski, T. B., Liu, Y., Tolu, S., Amengual, J. E. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-166929

  View details for Web of Science ID 000893223200148

• Editorial: Current Status and the Need for Acute and Chronic Modulation of Brain Circuits as Interventions in Neurological and Psychiatric Disorders FRONTIERS IN HUMAN NEUROSCIENCE Wei, Z. Z., Qiu, B., Song, X., Liu, Y. 2022; 16: 927382

  View details for DOI 10.3389/fnhum.2022.927382

  View details for Web of Science ID 000838123900001

  View details for PubMedID 35832874

  View details for PubMedCentralID PMC9271917

• Glucocorticoid-Resistant B-Cell Acute Lymphoblastic Leukemic Cells Can be Targeted By BCR-Signaling Inhibition Sarno, J., Domizi, P., Liu, Y., Merchant, M., Jedoui, D., Jager, A., Biondi, A., Gaipa, G., Bava, A., Davis, K. L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-150356

  View details for Web of Science ID 000736398802158

• Histone Acetyltransferase (HAT) Activator, YF2, Modulates the p53:BCL6 Axis and Antigen Presentation in Diffuse Large B-Cell Lymphomas Estrella, B., Liu, Y., Ricker, E. C., Pazos, M. A., Fiorito, J., Zuccarello, E., Calcagno, E., Honig, B., Arancio, O., Amengual, J. E. AMER SOC HEMATOLOGY. 2021

  View details for Web of Science ID 000736413900249

• Inhibition of Pre-BCR Signaling Mediates a Metabolic Switch in B-Cell Progenitor Acute Lymphoblastic Leukemia Liu, Y., Stuani, L., Jedoui, D., Merchant, M., Jager, A., Sarno, J., Mullighan, C. G., Hartmann, F. J., Bendall, S., Davis, K. L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-145956

  View details for Web of Science ID 000736398802156

• Hypomethylating Agents in Lymphoma. Current treatment options in oncology Cogan, J. C., Liu, Y., Amengual, J. E. 2020; 21 (8): 61

  Abstract

  Epigenetic mutations are frequent and pathogenic in select subtypes of lymphoma, and agents modulating DNA and histone methylation-such as inhibitors of DNMT and EZH2, respectively-have demonstrated promise in treating these diseases. In particular, lymphomas derived from the germinal center-GC-DLBCL, FL, and AITL-are all characterized by epigenetic derangements. In an effort to target these derangements, DNMT inhibitors have been investigated as a means of improving responsiveness to chemotherapy in DLBCL patients, or as monotherapy or in combination with other epigenetic agents in the treatment of TCL. Histone methyltransferase inhibitors have demonstrated effectiveness in R/R FL patients with EZH2-activating mutations. New treatment options that target the pathogenesis of disease are needed. HDAC inhibitors have been in the clinic for over a decade for the treatment of lymphoma, and now methyltransferase inhibitors are finding their niche for this disease.

  View details for DOI 10.1007/s11864-020-00761-9

  View details for PubMedID 32601883

• Chromatin-Remodeled State in Lymphoma. Current hematologic malignancy reports Liu, Y., Gonzalez, Y., Amengual, J. E. 2019; 14 (5): 439-450

  Abstract

  Emerging evidence has shown that epigenetic derangements might drive and promote tumorigenesis in various types of malignancies and is prevalent in both B cell and T cell lymphomas. The purpose of this review is to explain how the epigenetic derangements result in a chromatin-remodeled state in lymphoma and contribute to the biology and clinical features of these tumors.Studies have explored on the functional role of epigenetic derangements in chromatin remodeling and lymphomagenesis. For example, the haploinsufficiency of CREBBP facilitates malignant transformation in mice and directly implicates the importance to re-establish the physiologic acetylation level. New findings identified 4 prominent DLBCL subtypes, including EZB-GC-DLBCL subtype that enriched in mutations of CREBBP, EP300, KMT2D, and SWI/SNF complex genes. EZB subtype has a worse prognosis than other GCB-tumors. Moreover, the action of the histone modifiers as well as chromatin-remodeling factors (e.g., SWI/SNF complex) cooperates to influence the chromatin state resulting in transcription repression. Drugs that alter the epigenetic landscape have been approved in T cell lymphoma. In line with this finding, epigenetic lesions in histone modifiers have recently been uncovered in this disease, further confirming the vulnerability to the therapies targeting epigenetic derangements. Modulating the chromatin state by epigenetic-modifying agents provides precision-medicine opportunities to patients with lymphomas that depend on this biology.

  View details for DOI 10.1007/s11899-019-00541-9

  View details for PubMedID 31489524

  View details for PubMedCentralID PMC6842442

• Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas. Clinical cancer research : an official journal of the American Association for Cancer Research Lue, J. K., Prabhu, S. A., Liu, Y., Gonzalez, Y., Verma, A., Mundi, P. S., Abshiru, N., Camarillo, J. M., Mehta, S., Chen, E. I., Qiao, C., Nandakumar, R., Cremers, S., Kelleher, N. L., Elemento, O., Amengual, J. E. 2019; 25 (17): 5271-5283

  Abstract

  Both gain-of-function enhancer of zeste homolog 2 (EZH2) mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC)-derived lymphomas. We hypothesized that direct inhibition of EZH2 and histone deacetyltransferase (HDAC) would be synergistic in GC-derived lymphomas.Lymphoma cell lines (n = 21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by excess over bliss. Western blot, mass spectrometry, and coimmunoprecipitation were performed. A SU-DHL-10 xenograft model was utilized to validate in vitro findings. Pretreatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity.Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination were due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and was characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNA methyltransferase were associated with EZH2 activation.Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.

  View details for DOI 10.1158/1078-0432.CCR-18-3989

  View details for PubMedID 30979734

  View details for PubMedCentralID PMC6726529

• BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors. Cell reports Derenzini, E., Mondello, P., Erazo, T., Portelinha, A., Liu, Y., Scallion, M., Asgari, Z., Philip, J., Hilden, P., Valli, D., Rossi, A., Djaballah, H., Ouerfelli, O., de Stanchina, E., Seshan, V. E., Hendrickson, R. C., Younes, A. 2018; 24 (8): 2155-2166

  Abstract

  The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase β (GSK3β) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3β S9 inhibitory phosphorylation, resulting in increased β-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3β S9 phosphorylation levels and β-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3β S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3β regulation, providing a mechanistic rationale for combination strategies.

  View details for DOI 10.1016/j.celrep.2018.07.055

  View details for PubMedID 30134175

  View details for PubMedCentralID PMC7456333

• The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia Liu, Y., Abdul Razak, F. R., Terpstra, M., Chan, F. C., Saber, A., Nijland, M., van Imhoff, G., Visser, L., Gascoyne, R., Steidl, C., Kluiver, J., Diepstra, A., Kok, K., van den Berg, A. 2014; 28 (11): 2248-51

  View details for DOI 10.1038/leu.2014.201

  View details for PubMedID 24947018

• A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus NATURE COMMUNICATIONS Cozen, W., Timofeeva, M. N., Li, D., Diepstra, A., Hazelett, D., Delahaye-Sourdeix, M., Edlund, C. K., Franke, L., Rostgaard, K., Van den Berg, D. J., Cortessis, V. K., Smedby, K. E., Glaser, S. L., Westra, H., Robison, L. L., Mack, T. M., Ghesquieres, H., HWANG, A. E., Nieters, A., De Sanjose, S., Lightfoot, T., Becker, N., Maynadie, M., Foretova, L., ROMAN, E., Benavente, Y., RAND, K. A., NATHWANI, B. N., Glimelius, B., Staines, A., Boffetta, P., Link, B. K., Kiemeney, L., Ansell, S. M., Bhatia, S., Strong, L. C., Galan, P., Vatten, L., Habermann, T. M., Duell, E. J., Lake, A., Veenstra, R. N., Visser, L., Liu, Y., Urayama, K. Y., Montgomery, D., Gaborieau, V., Weiss, L. M., Byrnes, G., Lathrop, M., Cocco, P., Best, T., Skol, A. D., Adami, H., Melbye, M., Cerhan, J. R., Gallagher, A., Taylor, G. M., Slager, S. L., Brennan, P., Coetzee, G. A., Conti, D. V., Onel, K., Jarrett, R. F., Hjalgrim, H., van den Berg, A., Mckay, J. D. 2014; 5

  Abstract

  Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI)=0.76-0.86, Pcombined=3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

  View details for DOI 10.1038/ncomms4856

  View details for Web of Science ID 000338830700001

  View details for PubMedID 24920014

  View details for PubMedCentralID PMC4055950

• The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Seminars in cancer biology Liu, Y., Sattarzadeh, A., Diepstra, A., Visser, L., van den Berg, A. 2014; 24: 15-22

  Abstract

  Classical Hodgkin lymphoma (cHL) is characterized by a minority of tumor cells derived from germinal center B-cells and a vast majority of non-malignant reactive cells. The tumor cells show a loss of B-cell phenotype including lack of the B-cell receptor, which makes the tumor cells vulnerable to apoptosis. To overcome this threat, tumor cells and their precursors depend on anti-apoptotic and growth stimulating factors that are obtained via triggering of multiple membrane receptors. In addition, tumor cells shape the environment by producing a wide variety of chemokines and cytokines. These factors alter the composition of the microenvironment and modulate the nature and effectiveness of the infiltrating cells. The attracted cells enhance the pro-survival and growth stimulating signals for the tumor cells. To escape from an effective anti-tumor response tumor cells avoid recognition by T and NK cells, by downregulation of HLA molecules and modulating NK and T-cell receptors. In addition, the tumor cells produce immune suppressive cytokines that inhibit cytotoxic responses. In this review the relevance of the microenvironment in the pathogenesis of cHL will be discussed.

  View details for DOI 10.1016/j.semcancer.2013.07.002

  View details for PubMedID 23867303

• PML Nuclear Bodies and SATB1 Are Associated with HLA Class I Expression in EBV plus Hodgkin Lymphoma PLOS ONE Liu, Y., van den Berg, A., Veenstra, R., Rutgers, B., Nolte, I., van Imhoff, G., Visser, L., Diepstra, A. 2013; 8 (8): e72930

  Abstract

  Tumor cells of classical Hodgkin lymphoma (cHL) are characterized by a general loss of B cell phenotype, whereas antigen presenting properties are commonly retained. HLA class I is expressed in most EBV+ cHL cases, with an even enhanced expression in a proportion of the cases. Promyelocytic leukemia protein (PML) and special AT-rich region binding protein 1 (SATB1) are two global chromatin organizing proteins that have been shown to regulate HLA class I expression in Jurkat cells. We analyzed HLA class I, number of PML nuclear bodies (NBs) and SATB1 expression in tumor cells of 54 EBV+ cHL cases and used 27 EBV- cHL cases as controls. There was a significant difference in presence of HLA class I staining between EBV+ and EBV- cases (p<0.0001). We observed normal HLA class I expression in 35% of the EBV+ and in 19% of the EBV- cases. A stronger than normal HLA class I expression was observed in approximately 40% of EBV+ cHL and not in EBV- cHL cases. 36 EBV+ cHL cases contained less than 10 PML-NBs per tumor cell, whereas 16 cases contained more than 10 PML-NBs. The number of PML-NBs was positively correlated to the level of HLA class I expression (p<0.01). The percentage of SATB1 positive cells varied between 0% to 100% in tumor cells and was inversely correlated with the level of HLA class I expression, but only between normal and strong expression (p<0.05). Multivariable analysis indicated that the number of PML-NBs and the percentage of SATB1+ tumor cells are independent factors affecting HLA class I expression in EBV+ cHL. In conclusion, both PML and SATB1 are correlated to HLA class I expression levels in EBV+ cHL.

  View details for DOI 10.1371/journal.pone.0072930

  View details for Web of Science ID 000323734600043

  View details for PubMedID 24009715

  View details for PubMedCentralID PMC3757028

• IgG gene expression and its possible significance in prostate cancers. The Prostate Liu, Y., Chen, Z., Niu, N., Chang, Q., Deng, R., Korteweg, C., Gu, J. 2012; 72 (6): 690-701

  Abstract

  In spite of recent advances in treatment strategies, prostate cancer (PCa) remains the second leading cause of cancer death in men with its genetic and biologic behaviors still poorly understood. Recently, accumulating evidence indicates that cancer cells, as well as some normal cells can secret IgG. This study was designed to evaluate IgG gene expression and its possible significance in PCa tissue samples and cell lines.IgG expression was assessed by immunohistochemistry, in situ hybridization, immunofluorescence, RT-PCR, and Western blot. The possible significance of IgG was evaluated on tissue array and cell lines. To assess cell viability and proliferation, MTS assay was carried out. Apoptosis was evaluated with propidium iodide and annexin-V staining.Expressions of IgG and its related genes were detected in cell lines. Abundant gene expressions of Igγ and Igκ chain were detected in PCa tissue samples, but not in normal prostate tissues. In addition, IgG expression was significantly higher in PCa tissues than in the benign prostate hyperplasia tissues (P < 0.001). Igγ expression was positively correlated to Gleason score and histological grade (P < 0.05). Furthermore, in vitro experiments showed that anti-human monoclonal IgG antibody suppressed cell proliferation and increased apoptosis in cultured PCa cells.IgG gene expression in PCa is related to cell differentiation and clinical status. PCa cell produced IgG is involved in the biological behavior of this cancer and may serve as a useful marker for cancer cell differentiation and prognosis. Locally produced IgG could be a potential target for therapy.

  View details for DOI 10.1002/pros.21476

  View details for PubMedID 22430367

• Immunoglobulin G Locus Events in Soft Tissue Sarcoma Cell Lines PLOS ONE Chen, Z., Li, J., Xiao, Y., Zhang, J., Zhao, Y., Liu, Y., Ma, C., Qiu, Y., Luo, J., Huang, G., Korteweg, C., Gu, J. 2011; 6 (6): e21276

  Abstract

  Recently immunoglobulins (Igs) have been found to be expressed by cells other than B lymphocytes, including various human carcinoma cells. Sarcomas are derived from mesenchyme, and the knowledge about the occurrence of Ig production in sarcoma cells is very limited. Here we investigated the phenomenon of immunoglobulin G (IgG) expression and its molecular basis in 3 sarcoma cell lines. The mRNA transcripts of IgG heavy chain and kappa light chain were detected by RT-PCR. In addition, the expression of IgG proteins was confirmed by Western blot and immunofluorescence. Immuno-electron microscopy localized IgG to the cell membrane and rough endoplasmic reticulum. The essential enzymes required for gene rearrangement and class switch recombination, and IgG germ-line transcripts were also identified in these sarcoma cells. Chromatin immunoprecipitation results demonstrated histone H3 acetylation of both the recombination activating gene and Ig heavy chain regulatory elements. Collectively, these results confirmed IgG expression in sarcoma cells, the mechanism of which is very similar to that regulating IgG expression in B lymphocytes.

  View details for DOI 10.1371/journal.pone.0021276

  View details for Web of Science ID 000292035400018

  View details for PubMedID 21731691

  View details for PubMedCentralID PMC3121753

• Transcription factors E2A, FOXO1 and FOXP1 regulate recombination activating gene expression in cancer cells. PloS one Chen, Z., Xiao, Y., Zhang, J., Li, J., Liu, Y., Zhao, Y., Ma, C., Luo, J., Qiu, Y., Huang, G., Korteweg, C., Gu, J. 2011; 6 (5): e20475

  Abstract

  It has long been accepted that immunoglobulins (Igs) were produced by B lymphoid cells only. Recently Igs have been found to be expressed in various human cancer cells and promote tumor growth. Recombination activating gene 1 (RAG1) and RAG2, which are essential enzymes for initiating variable-diversity-joining segment recombination, have also been found to be expressed in cancer cells. However, the mechanism of RAG activation in these cancer cells has not been elucidated. Here, we investigated the regulatory mechanism of RAG expression in four human cancer cell lines by analyzing transcription factors that induce RAG activation in B cells. By RT-PCR, Western blot and immunofluorescence, we found that transcription factors E2A, FOXO1 and FOXP1 were expressed and localized to the nuclei of these cancer cells. Over-expression of E2A, FOXO1 or Foxp1 increased RAG expression, while RNA interference of E2A, FOXO1 or FOXP1 decreased RAG expression in the cancer cells. Chromatin immunoprecipitation experiments showed acetylation of RAG enhancer (Erag) and E2A, FOXO1 or FOXP1 were bound to Erag in vivo. These results indicate that in these cancer cells the transcription factors E2A, FOXO1 and FOXP1 regulate RAG expression, which initiates Ig gene rearrangement much in the way similar to B lymphocytes.

  View details for DOI 10.1371/journal.pone.0020475

  View details for PubMedID 21655267

  View details for PubMedCentralID PMC3105062

• Immunoglobulin G (IgG) Expression in Human Umbilical Cord Endothelial Cells JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY Zhao, Y., Liu, Y., Chen, Z., Korteweg, C., Gu, J. 2011; 59 (5): 474-488

  Abstract

  Traditional views hold that immunoglobulin G (IgG) in the human umbilical cord is internalized by human umbilical endothelial cells for passive immunity. In this study, the protein and mRNA transcripts of IgG were found in the cytoplasm of human umbilical endothelial cells by immunohistochemistry, in situ hybridization, and reverse transcription PCR (RT-PCR). The essential enzymes for IgG synthesis and assembling, RAG1 (recombination activating gene 1), RAG2, and variable (V), diversity (D), and joining (J) segments for recombination of IgG, were also found in these cells by RT-PCR and real-time PCR. These results indicate that umbilical endothelial cells are capable of synthesizing IgG with properties similar to those of immune cells and that they may play additional roles besides lining the vessels and transporting IgG.

  View details for DOI 10.1369/0022155411400871

  View details for Web of Science ID 000293703400002

  View details for PubMedID 21430258

  View details for PubMedCentralID PMC3201178