117 results on '"Benjamin G. Barwick"'
Search Results
2. Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis
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Carlos S. Moreno, Cynthia L. Winham, Mehrdad Alemozaffar, Emma R. Klein, Ismaheel O. Lawal, Olayinka A. Abiodun-Ojo, Dattatraya Patil, Benjamin G. Barwick, Yijian Huang, David M. Schuster, Martin G. Sanda, and Adeboye O. Osunkoya
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cancer genomics ,metastasis ,prostate cancer ,tumor heterogeneity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.
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- 2023
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3. Ten-eleven translocation protein 1 modulates medulloblastoma progression
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Hyerim Kim, Yunhee Kang, Yujing Li, Li Chen, Li Lin, Nicholas D. Johnson, Dan Zhu, M. Hope Robinson, Leon McSwain, Benjamin G. Barwick, Xianrui Yuan, Xinbin Liao, Jie Zhao, Zhiping Zhang, Qiang Shu, Jianjun Chen, Emily G. Allen, Anna M. Kenney, Robert C. Castellino, Erwin G. Van Meir, Karen N. Conneely, Paula M. Vertino, Peng Jin, and Jian Li
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Medulloblastoma ,5-hydroxymethylcytosine ,TET1 ,Stem-like property ,NANOG ,PDGF signaling pathway ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. Results We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. Conclusions These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.
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- 2021
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4. β adrenergic signaling regulates hematopoietic stem and progenitor cell commitment and therapy sensitivity in multiple myeloma
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Remya Nair, Vimal Subramaniam, Benjamin G. Barwick, Vikas A. Gupta, Shannon M. Matulis, Sagar Lonial, Lawrence H. Boise, Ajay K. Nooka, Kuzhali Muthumalaiappan, and Mala Shanmugam
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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5. Oncolytic herpes simplex virus infects myeloma cells in vitro and in vivo
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Jayeeta Ghose, Ada Dona, Mariam Murtadha, Emine Gulsen Gunes, Enrico Caserta, Ji Young Yoo, Luke Russell, Alena Cristina Jaime-Ramirez, Benjamin G. Barwick, Vikas A. Gupta, James F. Sanchez, Douglas W. Sborov, Steven T. Rosen, Amrita Krishnan, Lawrence H. Boise, Balveen Kaur, Craig C. Hofmeister, and Flavia Pichiorri
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oncolytic herpes simplex virus type 1 (oHSV-1) ,oncolytic virus (OV) therapy ,multiple myeloma ,HVEM ,NECTIN-1 ,malignant plasma cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP+ signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138+/CD38+ plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target.
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- 2021
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6. Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma
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Yanyan Gu, Benjamin G. Barwick, Mala Shanmugam, Craig C. Hofmeister, Jonathan Kaufman, Ajay Nooka, Vikas Gupta, Madhav Dhodapkar, Lawrence H. Boise, and Sagar Lonial
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.
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- 2020
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7. Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
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Richa Bajpai, Aditi Sharma, Abhinav Achreja, Claudia L. Edgar, Changyong Wei, Arusha A. Siddiqa, Vikas A. Gupta, Shannon M. Matulis, Samuel K. McBrayer, Anjali Mittal, Manali Rupji, Benjamin G. Barwick, Sagar Lonial, Ajay K. Nooka, Lawrence H. Boise, Deepak Nagrath, and Mala Shanmugam
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Science - Abstract
Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.
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- 2020
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8. Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma
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Yu-Hsiu T. Lin, Gregory P. Way, Benjamin G. Barwick, Margarette C. Mariano, Makeba Marcoulis, Ian D. Ferguson, Christoph Driessen, Lawrence H. Boise, Casey S. Greene, and Arun P. Wiita
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: A major driver of multiple myeloma (MM) is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employed an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in MM to inform precision medicine strategies. Unbiased phosphoproteomics initially revealed differential activation of kinases across MM cell lines and that sensitivity to mammalian target of rapamycin (mTOR) inhibition may be particularly dependent on mTOR kinase baseline activity. We further noted differential activity of immediate downstream effectors of Ras as a function of cell line genotype. We extended these observations to patient transcriptome data in the Multiple Myeloma Research Foundation CoMMpass study. A machine-learning–based classifier identified surprisingly divergent transcriptional outputs between NRAS- and KRAS-mutated tumors. Genetic dependency and gene expression analysis revealed mutated Ras as a selective vulnerability, but not other MAPK pathway genes. Transcriptional analysis further suggested that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs wild-type RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes, whereas RAS mutations overall carry no survival impact. We further developed an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between NRAS and KRAS mutants invisible to the genomic landscape. These results will lead to improved stratification of MM patients in precision medicine trials while also revealing unexplored modes of Ras biology in MM.
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- 2019
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9. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis
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Benjamin G. Barwick, Paola Neri, Nizar J. Bahlis, Ajay K. Nooka, Madhav V. Dhodapkar, David L. Jaye, Craig C. Hofmeister, Jonathan L. Kaufman, Vikas A. Gupta, Daniel Auclair, Jonathan J. Keats, Sagar Lonial, Paula M. Vertino, and Lawrence H. Boise
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Science - Abstract
Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.
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- 2019
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10. Multivariant Transcriptome Analysis Identifies Modules and Hub Genes Associated with Poor Outcomes in Newly Diagnosed Multiple Myeloma Patients
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Olayinka O. Adebayo, Eric B. Dammer, Courtney D. Dill, Adeyinka O. Adebayo, Saheed O. Oseni, Ti’ara L. Griffen, Adaugo Q. Ohandjo, Fengxia Yan, Sanjay Jain, Benjamin G. Barwick, Rajesh Singh, Lawrence H. Boise, and James W. Lillard, Jr.
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multiple myeloma ,chemoresistance ,ROC ,log-rank ,Kaplan–Meier ,WGCNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The molecular mechanisms underlying chemoresistance in some newly diagnosed multiple myeloma (MM) patients receiving standard therapies (lenalidomide, bortezomib, and dexamethasone) are poorly understood. Identifying clinically relevant gene networks associated with death due to MM may uncover novel mechanisms, drug targets, and prognostic biomarkers to improve the treatment of the disease. This study used data from the MMRF CoMMpass RNA-seq dataset (N = 270) for weighted gene co-expression network analysis (WGCNA), which identified 21 modules of co-expressed genes. Genes differentially expressed in patients with poor outcomes were assessed using two independent sample t-tests (dead and alive MM patients). The clinical performance of biomarker candidates was evaluated using overall survival via a log-rank Kaplan–Meier and ROC test. Four distinct modules (M10, M13, M15, and M20) were significantly correlated with MM vital status and differentially expressed between the dead (poor outcomes) and the alive MM patients within two years. The biological functions of modules positively correlated with death (M10, M13, and M20) were G-protein coupled receptor protein, cell–cell adhesion, cell cycle regulation genes, and cellular membrane fusion genes. In contrast, a negatively correlated module to MM mortality (M15) was the regulation of B-cell activation and lymphocyte differentiation. MM biomarkers CTAG2, MAGEA6, CCND2, NEK2, and E2F2 were co-expressed in positively correlated modules to MM vital status, which was associated with MM’s lower overall survival.
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- 2022
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11. B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation
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Benjamin G. Barwick, Christopher D. Scharer, Ryan J. Martinez, Madeline J. Price, Alexander N. Wein, Robert R. Haines, Alexander P. R. Bally, Jacob E. Kohlmeier, and Jeremy M. Boss
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Science - Abstract
DNA methylation is known to contribute to B cell differentiation, but de novo methylation has not been studied in this context. Here the authors use a conditional Dnmt3a/b knockout mouse to map the function of de novo DNA methylation in B cell differentiation and the development of humoral immunity.
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- 2018
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12. Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs
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Christopher D. Scharer, Benjamin G. Barwick, Muyao Guo, Alexander P. R. Bally, and Jeremy M. Boss
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Science - Abstract
During B cell differentiation, the role of different genomic loci in transcriptional and epigenetic regulation in vivo is not well defined. Here the authors use an in vivo B cell differentiation model to map cellular division-dependent cis-regulatory element road map with ATAC-seq.
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- 2018
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13. CD86 regulates myeloma cell survival
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Catherine M. Gavile, Benjamin G. Barwick, Scott Newman, Paola Neri, Ajay K. Nooka, Sagar Lonial, Kelvin P. Lee, and Lawrence H. Boise
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Although prognosis for patients with multiple myeloma has improved over the past decade, research toward discovery of new therapeutic avenues is important and could lead to a cure for this plasma cell malignancy. Here we show that blocking the CD28-CD86 pathway via silencing of either CD28 or CD86 leads to myeloma cell death. Inhibiting this pathway leads to downregulation of integrins and IRF4, a known myeloma survival factor. Our data also indicate that CD86, the canonical ligand in this pathway, has prosurvival activity that is dependent on its cytosolic domain. These findings indicate that targeting of this pathway is a promising therapeutic avenue for myeloma, because it leads to modulation of different processes important in cell viability.
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- 2017
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14. LSD1 protects against hippocampal and cortical neurodegeneration
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Michael A. Christopher, Dexter A. Myrick, Benjamin G. Barwick, Amanda K. Engstrom, Kirsten A. Porter-Stransky, Jeremy M. Boss, David Weinshenker, Allan I. Levey, and David J. Katz
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Science - Abstract
“LSD1 is a histone demethylase that plays many roles during development. Here, the authors provide evidence that loss of LSD1 in adult mice leads to paralysis and neurodegeneration in the hippocampus and cortex and suggest a potential link between LSD1 and human neurodegenerative disease.
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- 2017
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15. Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma
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Benjamin G. Barwick, Vikas A. Gupta, Paula M. Vertino, and Lawrence H. Boise
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multiple myeloma ,MGUS ,plasma cell ,B cell ,genetics ,epigenetics ,Immunologic diseases. Allergy ,RC581-607 - Abstract
B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma.
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- 2019
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16. Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias
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Ricardo de Matos Simoes, Ryosuke Shirasaki, Sondra L. Downey-Kopyscinski, Geoffrey M. Matthews, Benjamin G. Barwick, Vikas A. Gupta, Daphné Dupéré-Richer, Shizuka Yamano, Yiguo Hu, Michal Sheffer, Eugen Dhimolea, Olga Dashevsky, Sara Gandolfi, Kazuya Ishiguro, Robin M. Meyers, Jordan G. Bryan, Neekesh V. Dharia, Paul J. Hengeveld, Johanna B. Brüggenthies, Huihui Tang, Andrew J. Aguirre, Quinlan L. Sievers, Benjamin L. Ebert, Brian J. Glassner, Christopher J. Ott, James E. Bradner, Nicholas P. Kwiatkowski, Daniel Auclair, Joan Levy, Jonathan J. Keats, Richard W. J. Groen, Nathanael S. Gray, Aedin C. Culhane, James M. McFarland, Joshua M. Dempster, Jonathan D. Licht, Lawrence H. Boise, William C. Hahn, Francisca Vazquez, Aviad Tsherniak, Constantine S. Mitsiades, Hematology laboratory, AMS - Tissue Function & Regeneration, and CCA - Cancer biology and immunology
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Cancer Research ,Oncology - Abstract
Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies that have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. Here we systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) studies in 19 MM versus hundreds of non-MM lines and identified 116 genes whose disruption more significantly affects MM cell fitness compared with other malignancies. These genes, some known, others not previously linked to MM, encode transcription factors, chromatin modifiers, endoplasmic reticulum components, metabolic regulators or signaling molecules. Most of these genes are not among the top amplified, overexpressed or mutated in MM. Functional genomics approaches thus define new therapeutic targets in MM not readily identifiable by standard genomic, transcriptional or epigenetic profiling analyses.
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- 2023
17. Data from Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia
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Madhav V. Dhodapkar, Kavita M. Dhodapkar, Sagar Lonial, Lawrence H. Boise, Stephen M. Ansell, Leonard T. Heffner, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Vikas A. Gupta, Samuel S. McCachren, Julia Manalo, Benjamin G. Barwick, Katherine E. Pendleton, Allison R. Carr, Ajay K. Nooka, and Akhilesh Kaushal
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Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation–specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells.Significance:These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre–B progenitor cells and suggest a novel model for WM pathogenesis.This article is highlighted in the In This Issue feature, p. 549
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- 2023
18. Supplementary Data from Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia
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Madhav V. Dhodapkar, Kavita M. Dhodapkar, Sagar Lonial, Lawrence H. Boise, Stephen M. Ansell, Leonard T. Heffner, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Vikas A. Gupta, Samuel S. McCachren, Julia Manalo, Benjamin G. Barwick, Katherine E. Pendleton, Allison R. Carr, Ajay K. Nooka, and Akhilesh Kaushal
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supplementary figs 1-25 and supplementary tables 1-3
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- 2023
19. Supplementary Data from PDZ Proteins SCRIB and DLG1 Regulate Myeloma Cell Surface CD86 Expression, Growth, and Survival
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Lawrence H. Boise, Kelvin P. Lee, Benjamin G. Barwick, Catherine M. Gavile, and Tyler Moser-Katz
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Supplementary Data from PDZ Proteins SCRIB and DLG1 Regulate Myeloma Cell Surface CD86 Expression, Growth, and Survival
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- 2023
20. Data from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Purpose:Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome.Experimental Design:CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1–6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297).Results:Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma.Conclusions:These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.
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- 2023
21. Supplementary Data 6 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Enrichment of transcription factor consensus binding motifs in regulatory elements predictive of gene expression associated with poor overall survival.
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- 2023
22. Supplementary Data 4 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Correlation of regulatory element transcription and gene expression in CoMMpass specimens.
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- 2023
23. Supplementary Data 8 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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ATAC-seq data for Emory patients.
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- 2023
24. Supplementary Data 1 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Correlation of chromatin accessibility and gene expression for the 5% most variably expressed genes.
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- 2023
25. Supplementary Data 5 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Regulatory elements predictive of gene expression for genes prognostic of overall survival in CoMMpass.
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- 2023
26. Supplementary Data 2 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Regulatory element transcription in newly diagnosed myelomas from CoMMpass.
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- 2023
27. Supplementary Data 3 from Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Lawrence H. Boise, Paula M. Vertino, Sagar Lonial, Jonathan J. Keats, Ajay K. Nooka, Craig C. Hofmeister, Yin C. Lin, Karen N. Conneely, David L. Jaye, Yanyan Gu, Doris R. Powell, Jonathan C. Patton, Shannon M. Matulis, Vikas A. Gupta, and Benjamin G. Barwick
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Gene set enrichment analysis of transcribed regulatory elements in CoMMpass.
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- 2023
28. Inhibition of NADPH Oxidase-ROS Signal using Hyaluronic Acid Nanoparticles for Overcoming Radioresistance in Cancer Therapy
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Lei Zhu, Yi Zhao, Tongrui Liu, Minglong Chen, Wei Ping Qian, Binghua Jiang, Benjamin G. Barwick, Lumeng Zhang, Toncred M Styblo, Xiaoxian Li, and Lily Yang
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General Engineering ,General Physics and Astronomy ,Mice, Nude ,NADPH Oxidases ,Breast Neoplasms ,Radiation Tolerance ,Mice ,Animals ,Humans ,Nanoparticles ,General Materials Science ,Female ,Hyaluronic Acid ,Reactive Oxygen Species - Abstract
Upregulation of NADPH oxidases (NOXs) in cancer cells leads to chronic increase in intracellular reactive oxygen species (ROS) and adaptation to a high ROS level for cell survival and, thereby, low sensitivity to radiotherapy. To overcome resistance to radiotherapy, we have developed a bioactive and CD44 targeted hyaluronic acid nanoparticle encapsulated with an NOX inhibitor, GKT831 (HANP/GKT831). We found that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 alone in cancer cells. Systemic delivery of HANP/GKT831 led to the targeted accumulation in breast cancer patient derived xenograft (PDX) tumors in nude mice. Importantly, the combination of systemic delivery of HANP/GKT831 with a low dose of local radiotherapy significantly enhanced tumor growth inhibition in breast cancer PDX models. Our results showed that HANP/GKT831 primed tumor cells to radiation-induced DNA damage and cell death by downregulation of DNA repair function and oncogenic signal pathways.
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- 2022
29. Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia
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Ajay K. Nooka, Samuel S. McCachren, Vikas Gupta, Sagar Lonial, Kavita M. Dhodapkar, Stephen M. Ansell, Lawrence H. Boise, Leonard T. Heffner, Julia Manalo, Akhilesh Kaushal, Allison R. Carr, Jonathan L. Kaufman, Nisha Joseph, Craig C. Hofmeister, Katherine E. Pendleton, Madhav V. Dhodapkar, and Benjamin G. Barwick
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Inflammation ,B-Lymphocytes ,Myeloid ,Clone (cell biology) ,Waldenstrom macroglobulinemia ,Oncogenes ,General Medicine ,Biology ,medicine.disease ,Haematopoiesis ,medicine.anatomical_structure ,Gammopathy ,Myeloid Differentiation Factor 88 ,Tumor Microenvironment ,Cancer research ,medicine ,Humans ,Bone marrow ,Waldenstrom Macroglobulinemia ,Progenitor cell ,medicine.symptom ,Research Articles - Abstract
Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation–specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells.Significance:These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre–B progenitor cells and suggest a novel model for WM pathogenesis.This article is highlighted in the In This Issue feature, p. 549
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- 2021
30. Therapeutic implications of mitochondrial stress–induced proteasome inhibitor resistance in multiple myeloma
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Aditi Sharma, Remya Nair, Abhinav Achreja, Anjali Mittal, Pulkit Gupta, Kamakshi Balakrishnan, Claudia L. Edgar, Olamide Animasahun, Bhakti Dwivedi, Benjamin G. Barwick, Vikas A. Gupta, Shannon M. Matulis, Manoj Bhasin, Sagar Lonial, Ajay K. Nooka, Arun P. Wiita, Lawrence H. Boise, Deepak Nagrath, and Mala Shanmugam
- Subjects
Sulfonamides ,Multidisciplinary ,Glutamates ,Proto-Oncogene Proteins c-bcl-2 ,Cell Line, Tumor ,Cystine ,Humans ,Bridged Bicyclo Compounds, Heterocyclic ,Multiple Myeloma ,Proteasome Inhibitors ,Antiporters - Abstract
The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response–dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter SLC7A11 , and analysis of patient single-cell RNA-seq shows that clusters with low ETC gene expression correlate with higher SLC7A11 expression. Furthermore, erastin or venetoclax treatment diminishes mitochondrial stress–induced PI resistance. In sum, our work demonstrates that mitochondrial stress promotes PI resistance and underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic state.
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- 2022
31. Abstract 3552: YAP-TEAD2 binding mediates therapy resistance in RAS-driven neuroblastoma
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Jenny Shim, Andrew Ho, Hunter C. Jonus, Adeiye A. Pilgrim, Benjamin G. Barwick, Tracy T. Tang, Lawrence H. Boise, and Kelly C. Goldsmith
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Cancer Research ,Oncology - Abstract
Background/Objectives: Despite intensive multimodal therapy, greater than 50% of children with high-risk neuroblastoma (HR NB) relapse with incurable disease. Next generation sequencing of primary HR NB tumors identified an increase in activating mutations in the RAS/RAF/MAPK pathway. Moreover, gene set enrichment analyses showed a significant decrease in expression of genes suppressed by the Yes-Associated Protein (YAP) at relapse, suggesting increased YAP transcriptional repression. YAP binds with TEAD family transcription factors to regulate gene expression. We have shown that YAP promotes chemotherapy and MEK inhibitor resistance in RAS-mutated NB tumors in vivo by suppressing the expression of Harakiri (HRK), a BH3-only pro-apoptotic protein activated in response to tumor environmental stress such as serum starvation. Our overall objective is to elucidate how YAP represses HRK and tumor suppressor genes globally, and to enhance MEK inhibitor potency by combining MEK inhibition with agents that inhibit YAP or induce HRK to restore the tumor environmental stress response and apoptosis in RAS-mutated NB. Design/Methods: We used publicly available databases to identify TEAD binding sites on the HRK gene locus in NB. To assess the global state of methylation, we treated NB cells, SK-N-AS (NRASQ61K mutation, MYCN non-amplified) and NLF (NF1 deletion, MYCN amplified), with demethylating agent azacitidine and evaluated HRK expression. To identify the specific TEAD (1-4) binding partner to YAP, we performed siRNA and co-immunoprecipitation studies. We further tested novel YAP-TEAD small molecule inhibitors with varying TEAD1-4 inhibition specificity in SK-N-AS and NLF cells in vitro. Results: We observed that TEAD binds near cis-regulatory regions on the HRK gene locus in NB. We found that HRK expression is restored when SK-N-AS and NLF cells are treated with azacitidine despite YAP expression increasing. We also identified TEAD2 as the specific binding partner to YAP in NB and found that TEAD2 is necessary for HRK regulation. Novel YAP-TEAD small molecule inhibitors affect NB cell viability under serum-deprived conditions in vitro, especially the inhibitor with highest specificity against TEAD2, and affect YAP-TEAD downstream targets. Conclusions: YAP-TEAD2 binding is essential for HRK regulation in RAS-mutated NB and thus is a logical therapeutic target to restore therapy response. Further studies are ongoing to test YAP-TEAD small molecule inhibitors in combination with MEK inhibitors and in vivo. Citation Format: Jenny Shim, Andrew Ho, Hunter C. Jonus, Adeiye A. Pilgrim, Benjamin G. Barwick, Tracy T. Tang, Lawrence H. Boise, Kelly C. Goldsmith. YAP-TEAD2 binding mediates therapy resistance in RAS-driven neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3552.
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- 2023
32. The Murine MHC Class II Super Enhancer IA/IE-SE Contains a Functionally Redundant CTCF-Binding Component and a Novel Element Critical for Maximal Expression
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Christopher D. Scharer, Alexander P. R. Bally, Dillon G. Patterson, Parimal Majumder, Jeremy M. Boss, Joshua T. Lee, and Benjamin G. Barwick
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Mice, Knockout ,CCCTC-Binding Factor ,biology ,Genes, MHC Class II ,Immunology ,Promoter ,Insulator (genetics) ,Article ,HLA-DQ alpha-Chains ,Cell biology ,Chromatin ,Mice, Inbred C57BL ,Mice ,Histone ,Super-enhancer ,CTCF ,Gene expression ,biology.protein ,Animals ,Immunology and Allergy ,Gene ,HLA-DRB1 Chains - Abstract
In both humans and mice, CTCF-binding elements form a series of interacting loops across the MHC class II (MHC-II) locus, and CTCF is required for maximal MHC-II gene expression. In humans, a CTCF-bound chromatin insulator termed XL9 and a super enhancer (SE) DR/DQ-SE situated in the intergenic region between HLA-DRB1 and HLA-DQA1 play critical roles in regulating MHC-II expression. In this study, we identify a similar SE, termed IA/IE-SE, located between H2-Eb1 and H2-Aa of the mouse that contains a CTCF site (C15) and a novel region of high histone H3K27 acetylation. A genetic knockout of C15 was created and its role on MHC-II expression tested on immune cells. We found that C15 deletion did not alter MHC-II expression in B cells, macrophages, and macrophages treated with IFN-γ because of functional redundancy of the remaining MHC-II CTCF sites. Surprisingly, embryonic fibroblasts derived from C15-deleted mice failed to induce MHC-II gene expression in response to IFN-γ, suggesting that at least in this developmental lineage, C15 was required. Examination of the three-dimensional interactions with C15 and the H2-Eb1 and H2-Aa promoters identified interactions within the novel region of high histone acetylation within the IA/IE-SE (termed N1) that contains a PU.1 binding site. CRISPR/Cas9 deletion of N1 altered chromatin interactions across the locus and resulted in reduced MHC-II expression. Together, these data demonstrate the functional redundancy of the MHC-II CTCF elements and identify a functionally conserved SE that is critical for maximal expression of MHC-II genes.
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- 2021
33. CD8
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Nataliya, Prokhnevska, Maria A, Cardenas, Rajesh M, Valanparambil, Ewelina, Sobierajska, Benjamin G, Barwick, Caroline, Jansen, Adriana, Reyes Moon, Petra, Gregorova, Luke, delBalzo, Rachel, Greenwald, Mehmet Asim, Bilen, Mehrdad, Alemozaffar, Shreyas, Joshi, Cara, Cimmino, Christian, Larsen, Viraj, Master, Martin, Sanda, and Haydn, Kissick
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Article - Abstract
Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8(+) T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1(+) stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8(+) T cells. Murine tumor models revealed that tumor-specific CD8(+) T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8(+) T cell activation in response to cancer is different from that of canonical CD8(+) T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8(+) T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.
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- 2022
34. Chromatin Accessibility Identifies Regulatory Elements Predictive of Gene Expression and Disease Outcome in Multiple Myeloma
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Karen N. Conneely, Shannon M. Matulis, Yanyan Gu, Benjamin G. Barwick, Ajay K. Nooka, Craig C. Hofmeister, Jonathan C. Patton, Vikas Gupta, Sagar Lonial, Jonathan J Keats, Paula M. Vertino, Lawrence H. Boise, Doris R. Powell, David L. Jaye, and Yin C. Lin
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0301 basic medicine ,Cancer Research ,Gene Expression ,Biology ,Article ,Epigenome ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Transcription (biology) ,hemic and lymphatic diseases ,Gene expression ,medicine ,Humans ,Enhancer ,Gene ,Multiple myeloma ,Oncogene ,Sequence Analysis, RNA ,Prognosis ,medicine.disease ,Chromatin ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Feasibility Studies ,RNA ,Multiple Myeloma - Abstract
Purpose: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. Experimental Design: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for 1–6 months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA sequencing (RNA-seq) and assay for transpose accessible chromatin sequencing (ATAC-seq). Chromatin accessible regions were used to identify regulatory RNA expression in more than 700 samples from newly diagnosed patients in the Multiple Myeloma Research Foundation CoMMpass trial (NCT01454297). Results: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. More than 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with immunoglobulin heavy chain translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. Conclusions: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.
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- 2021
35. Oncolytic herpes simplex virus infects myeloma cells in vitro and in vivo
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Vikas Gupta, Balveen Kaur, James F. Sanchez, Luke Russell, Ji Young Yoo, Steven T. Rosen, Alena Cristina Jaime-Ramirez, Enrico Caserta, Ada Dona, Jayeeta Ghose, Amrita Krishnan, Douglas W. Sborov, Emine Gulsen Gunes, Benjamin G. Barwick, Flavia Pichiorri, Mariam Murtadha, Lawrence H. Boise, and Craig C. Hofmeister
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0301 basic medicine ,Cancer Research ,bone marrow ,Biology ,CD38 ,HVEM ,NECTIN-1 ,medicine.disease_cause ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,malignant plasma cells ,medicine ,Pharmacology (medical) ,Tropism ,oncolytic virus ,apoptosis ,oncolytic herpes simplex virus type 1 (oHSV-1) ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncolytic virus ,multiple myeloma ,oncolytic virus (OV) therapy ,030104 developmental biology ,Herpes simplex virus ,medicine.anatomical_structure ,Oncology ,Viral replication ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Original Article ,Bone marrow ,recombinant virus - Abstract
Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP+ signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138+/CD38+ plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target., Graphical Abstract, Receptors of oncolytic herpes simplex virus (oHSV-1), NECTIN-1, and HVEM are expressed on multiple myeloma (MM) cells. Whereas NECTIN-1 expression is variable among MM cells, HVEM is ubiquitously and highly expressed on all samples tested. However, no viral replication occurred. Instead, oHSV-1 induced MM cell apoptosis via caspase-3 cleavage.
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- 2021
36. Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression
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Craig C. Hofmeister, Lawrence H. Boise, Ryosuke Shirasaki, Jonathan L. Kaufman, Nisha Joseph, Benjamin G. Barwick, David L. Jaye, Jonathan J Keats, Constantine S. Mitsiades, Leonard T. Heffner, Benjamin Oberlton, Ajay K. Nooka, Vikas Gupta, Sagar Lonial, Shannon M. Matulis, and Madhav V. Dhodapkar
- Subjects
Immunology ,Cell ,Biology ,Biochemistry ,Translocation, Genetic ,Epigenesis, Genetic ,chemistry.chemical_compound ,Cyclin D1 ,Cell Line, Tumor ,hemic and lymphatic diseases ,BATF ,medicine ,Humans ,B cell ,Multiple myeloma ,Chromosomes, Human, Pair 14 ,B-Lymphocytes ,Sulfonamides ,Gene knockdown ,Venetoclax ,Chromosomes, Human, Pair 11 ,Cell Biology ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Basic-Leucine Zipper Transcription Factors ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cell culture ,Gene Knockdown Techniques ,Cancer research ,Multiple Myeloma - Abstract
Venetoclax is a highly potent, selective BCL2 inhibitor capable of inducing apoptosis in cells dependent on BCL2 for survival. Most myeloma is MCL1-dependent; however, a subset of myeloma enriched for translocation t(11;14) is codependent on BCL2 and thus sensitive to venetoclax. The biology underlying this heterogeneity remains poorly understood. We show that knockdown of cyclin D1 does not induce resistance to venetoclax, arguing against a direct role for cyclin D1 in venetoclax sensitivity. To identify other factors contributing to venetoclax response, we studied a panel of 31 myeloma cell lines and 25 patient samples tested for venetoclax sensitivity. In cell lines, we corroborated our previous observation that BIM binding to BCL2 correlates with venetoclax response and further showed that knockout of BIM results in decreased venetoclax sensitivity. RNA-sequencing analysis identified expression of B-cell genes as enriched in venetoclax-sensitive myeloma, although no single gene consistently delineated sensitive and resistant cells. However, a panel of cell surface makers correlated well with ex vivo prediction of venetoclax response in 21 patient samples and may serve as a biomarker independent of t(11;14). Assay for transposase-accessible chromatin sequencing of myeloma cell lines also identified an epigenetic program in venetoclax-sensitive cells that was more similar to B cells than that of venetoclax-resistant cells, as well as enrichment for basic leucine zipper domain–binding motifs such as BATF. Together, these data indicate that remnants of B-cell biology are associated with BCL2 dependency and point to novel biomarkers of venetoclax-sensitive myeloma independent of t(11;14).
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- 2021
37. CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor
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Nataliya Prokhnevska, Maria A. Cardenas, Rajesh M. Valanparambil, Ewelina Sobierajska, Benjamin G. Barwick, Caroline Jansen, Adriana Reyes Moon, Petra Gregorova, Luke delBalzo, Rachel Greenwald, Mehmet Asim Bilen, Mehrdad Alemozaffar, Shreyas Joshi, Cara Cimmino, Christian Larsen, Viraj Master, Martin Sanda, and Haydn Kissick
- Subjects
Infectious Diseases ,Immunology ,Immunology and Allergy - Published
- 2023
38. Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
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Benjamin G. Barwick, Arusha A. Siddiqa, Anjali Mittal, Samuel K. McBrayer, Changyong Wei, Mala Shanmugam, Deepak Nagrath, Aditi Sharma, Ajay K. Nooka, Richa Bajpai, Abhinav Achreja, Claudia L. Edgar, Vikas Gupta, Sagar Lonial, Manali Rupji, Shannon M. Matulis, and Lawrence H. Boise
- Subjects
0301 basic medicine ,Cancer therapy ,Molecular biology ,Mutant ,General Physics and Astronomy ,Chromosomal translocation ,Myeloma ,Pharmacology ,Translocation, Genetic ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Science ,Multiple myeloma ,Thenoyltrifluoroacetone ,Sulfonamides ,Multidisciplinary ,Chemistry ,Electron Transport Complex II ,Prognosis ,3. Good health ,Mitochondria ,Enzymes ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Multiple Myeloma ,Oxidation-Reduction ,musculoskeletal diseases ,Cell biology ,Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,Electron Transport ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Chromosomes, Human, Pair 14 ,Electron Transport Complex I ,Venetoclax ,Chromosomes, Human, Pair 11 ,Patient Selection ,Antagonist ,Membrane Proteins ,General Chemistry ,Metabolism ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,030104 developmental biology ,Cell culture ,Drug Resistance, Neoplasm ,Mutation ,lcsh:Q - Abstract
The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the ‘primed’ state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy., Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.
- Published
- 2020
39. Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone
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Madhav V. Dhodapkar, Jonathan L. Kaufman, Vikas Gupta, Sagar Lonial, Ajay K. Nooka, Zhengjia Chen, Jiayi Wu, David L. Jaye, Leonard T. Heffner, Craig C. Hofmeister, Subir Goyal, Nisha Joseph, Lawrence H. Boise, Timothy M. Schmidt, Benjamin G. Barwick, and Leon Bernal
- Subjects
Oncology ,Male ,Myeloma ,Kaplan-Meier Estimate ,Dexamethasone ,Bortezomib ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Chromosome Duplication ,Cancer genomics ,Medicine ,Lenalidomide ,Multiple myeloma ,Aged, 80 and over ,0303 health sciences ,Hematology ,Middle Aged ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Cancer therapeutic resistance ,Treatment Outcome ,Chromosomes, Human, Pair 1 ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Multiple Myeloma ,medicine.drug ,medicine.medical_specialty ,DNA Copy Number Variations ,Context (language use) ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,Internal medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Association Studies ,030304 developmental biology ,Aged ,Proportional Hazards Models ,business.industry ,Proportional hazards model ,Significant difference ,Chromosome ,medicine.disease ,business - Abstract
Gain of chromosome 1q (+1q) is commonly identified in multiple myeloma and has been associated with inferior outcomes. However, the prognostic implication of +1q has not been evaluated in the setting of standard triplet regimens. We retrospectively analyzed 201 consecutive patients with newly diagnosed myeloma who received induction with lenalidomide, bortezomib, and dexamethasone (RVD) and were tested for +1q at diagnosis by fluorescent in-situ hybridization. Patients with +1q (n = 94), compared to those without +1q (n = 107), had shorter median progression-free survival (PFS) (41.9 months vs 65.1 months, p = 0.002, HR = 1.90) and overall survival (median not reached (NR) for either arm, p = 0.003, HR 2.69). In subgroup analyses, patients with co-occurring +1q and t(4;14), t(14;16) or del(17p) or with 4 or more copies of 1q had significantly worse PFS (25.1 months and 34.6 months, p p = 0.0063, respectively), whereas patients with three copies and no other high-risk cytogenetic abnormalities had no significant difference in PFS. These data suggest that when treated with RVD induction, patients with +1q should be considered at very high risk for early progression in multiple myeloma when ≥4 copies are detected or in the context of other high-risk cytogenetic abnormalities.
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- 2019
40. IMiDs Synergize with EP300 Inhibition to Disrupt the Ikzf/MYC/IRF4 Axis in Multiple Myeloma
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Seth J Welsh, Benjamin G Barwick, Erin Meermeier, Daniel Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Victoria Marie Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Rodrigo Fonseca, Kennedi Todd, Sochilt Brown, Yuliza Tafoya Alvarado, Zachary Hammond, Nicklus Cuc, Courtney Wittenberg, Camille Herzog, Lawrence H. Boise, Nizar J. Bahlis, Paola Neri, W. Michael Kuehl, Marta Chesi, and P. Leif Bergsagel
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
41. Whole‐genome analysis of TET dioxygenase function in regulatory T cells
- Author
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Edahí González-Avalos, Daniela Samaniego-Castruita, Xiaojing Yue, Xiang Li, Benjamin G. Barwick, and Anjana Rao
- Subjects
Cellular differentiation ,Immunology ,vitamin C ,chemical and pharmacologic phenomena ,Biochemistry ,Chromatin, Epigenetics, Genomics & Functional Genomics ,T-Lymphocytes, Regulatory ,Article ,Dioxygenases ,Transforming Growth Factor beta ,Genetics ,Epigenetics ,Molecular Biology ,Gene ,Transcription factor ,STAT5 ,biology ,epigenetics ,Activator (genetics) ,Chemistry ,FOXP3 ,hemic and immune systems ,Cell Differentiation ,Forkhead Transcription Factors ,Articles ,Chromatin ,Cell biology ,Gene Expression Regulation ,IL‐2 ,biology.protein ,TET proteins ,STAT5 signaling ,Treg cells ,Signal Transduction - Abstract
TET methylcytosine dioxygenases are essential for the stability and function of regulatory T cells (Treg cells), which maintain immune homeostasis and self‐tolerance and express the lineage‐determining transcription factor Foxp3. Here, we use whole‐genome analyses to show that the transcriptional program and epigenetic features (DNA modification, chromatin accessibility) of Treg cells are attenuated in the absence of Tet2 and Tet3. Conversely, the addition of the TET activator vitamin C during TGFβ‐induced iTreg cell differentiation in vitro potentiates the expression of Treg signature genes and alters the epigenetic landscape to better resemble that of Treg cells generated in vivo. Vitamin C enhances IL‐2 responsiveness in iTreg cells by increasing IL2Rα expression, STAT5 phosphorylation, and STAT5 binding, mimicking the IL‐2/STAT5 dependence of Treg cells generated in vivo. In summary, TET proteins play essential roles in maintaining Treg molecular features and promoting their dependence on IL‐2. TET activity during endogenous Treg development and potentiation of TET activity by vitamin C during iTreg differentiation are necessary to maintain the transcriptional and epigenetic features of Treg cells., Genomic analyses of wildtype and TET‐deficient Treg cells, and iTreg cells treated with the TET activator Vitamin C, show that TET proteins are essential for the maintenance of Treg signatures and IL‐2/STAT5 signaling.
- Published
- 2021
42. Ten-eleven translocation protein 1 modulates medulloblastoma progression
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Erwin G. Van Meir, Jian Li, Qiang Shu, Karen N. Conneely, Emily G. Allen, Dan Zhu, Yunhee Kang, Li Chen, Jie Zhao, Robert C. Castellino, Li Lin, Yujing Li, M. Hope Robinson, Peng Jin, Leon F. McSwain, Benjamin G. Barwick, Paula M. Vertino, Anna Kenney, Zhiping Zhang, Jianjun Chen, Xianrui Yuan, Nicholas D. Johnson, Xinbin Liao, and Hyerim Kim
- Subjects
QH301-705.5 ,Somatic cell ,Mice, Transgenic ,Chromosomal translocation ,QH426-470 ,Biology ,medicine.disease_cause ,Epigenesis, Genetic ,Mixed Function Oxygenases ,Mice ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,Genetics ,medicine ,Animals ,Humans ,5-hydroxymethylcytosine ,Epigenetics ,Nucleotide Motifs ,Biology (General) ,Gene ,5-Hydroxymethylcytosine ,Medulloblastoma ,PDGF signaling pathway ,Gene Expression Profiling ,Research ,Stem-like property ,Computational Biology ,DNA Methylation ,Prognosis ,medicine.disease ,TET1 ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,NANOG ,chemistry ,5-Methylcytosine ,Disease Progression ,Cancer research ,CpG Islands ,Disease Susceptibility ,Databases, Nucleic Acid ,Smoothened ,Carcinogenesis - Abstract
BackgroundMedulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.ResultsWe investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout ofTet1in the smoothened (SmoA1)mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacologicalTet1inhibition reduces cell viability andplatelet-derived growth factorsignaling pathway-associated genes.ConclusionsThese results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.
- Published
- 2021
43. Epigenetic programming underpins B cell dysfunction in human SLE
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Chungwen Wei, Benjamin G. Barwick, Jeremy M. Boss, Christopher D. Scharer, Bridget E. Neary, Tsuneo Deguchi, Iñaki Sanz, Tian Mi, Arezou Khosroshahi, F. Eun-Hyung Lee, Scott A. Jenks, Dillon G. Patterson, Emily L. Blalock, Sakeenah L. Hicks, and Kevin S. Cashman
- Subjects
0301 basic medicine ,Immunology ,B-Lymphocyte Subsets ,Biology ,Article ,Epigenesis, Genetic ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,medicine ,Immunology and Allergy ,Humans ,Lupus Erythematosus, Systemic ,Epigenetics ,skin and connective tissue diseases ,B cell ,Epigenesis ,Lupus erythematosus ,Effector ,Epigenome ,DNA Methylation ,medicine.disease ,Chromatin Assembly and Disassembly ,Chromatin ,Cell biology ,Transcription Factor AP-1 ,030104 developmental biology ,medicine.anatomical_structure ,Early Growth Response Transcription Factors ,030215 immunology - Abstract
Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.
- Published
- 2019
44. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis
- Author
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David L. Jaye, Craig C. Hofmeister, Paola Neri, Nizar J. Bahlis, Daniel Auclair, Paula M. Vertino, Lawrence H. Boise, Ajay K. Nooka, Madhav V. Dhodapkar, Benjamin G. Barwick, Jonathan L. Kaufman, Vikas Gupta, Sagar Lonial, and Jonathan J Keats
- Subjects
0301 basic medicine ,General Physics and Astronomy ,Myeloma ,Chromosomal translocation ,02 engineering and technology ,Disease ,Translocation, Genetic ,Tumour biomarkers ,Recurrence ,hemic and lymphatic diseases ,Cancer genomics ,lcsh:Science ,Lenalidomide ,Multiple myeloma ,Multidisciplinary ,biology ,Prognosis ,021001 nanoscience & nanotechnology ,Thalidomide ,3. Good health ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,Myeloma Proteins ,Antibody ,Multiple Myeloma ,0210 nano-technology ,Protein Binding ,DNA Copy Number Variations ,Science ,Plasma Cells ,Antineoplastic Agents ,Locus (genetics) ,Malignancy ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,Ikaros Transcription Factor ,03 medical and health sciences ,Immunoglobulin lambda-Chains ,medicine ,Humans ,Immunologic Factors ,Survival analysis ,Whole Genome Sequencing ,Genome, Human ,business.industry ,General Chemistry ,Epigenome ,medicine.disease ,Survival Analysis ,030104 developmental biology ,Drug Resistance, Neoplasm ,Genetic Loci ,Cancer research ,biology.protein ,lcsh:Q ,business - Abstract
Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance., Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.
- Published
- 2019
45. Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer
- Author
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Daqing Wu, Hsiao Rong Chen, Lawrence H. Boise, Jeanne Kowalski, Weiping Qian, Yixiang Li, Omer Kucuk, Menglin Li, Qiao Wu, Lily Yang, Wei Zhou, Adeboye O. Osunkoya, Lin Xie, Xin Li, Changying Fu, Yichao Zhao, Jing Chen, Baotong Zhang, Benjamin G. Barwick, Jin-Tang Dong, Siyuan Xia, and Paula M. Vertino
- Subjects
Male ,0301 basic medicine ,Benzylamines ,Carcinogenesis ,General Physics and Astronomy ,Docetaxel ,Cyclams ,CXCR4 ,Mice ,Prostate cancer ,0302 clinical medicine ,Osteogenesis ,Transforming Growth Factor beta ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Multidisciplinary ,Bone metastasis ,Acetylation ,Interleukin-11 ,Prostatic Neoplasms, Castration-Resistant ,Cancer therapeutic resistance ,030220 oncology & carcinogenesis ,Signal Transduction ,medicine.drug ,Receptors, CXCR4 ,Epithelial-Mesenchymal Transition ,Science ,Kruppel-Like Transcription Factors ,Bone Neoplasms ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Paracrine signalling ,Cell Line, Tumor ,Animals ,Humans ,Transcription factor ,business.industry ,Bone metastases ,Plerixafor ,General Chemistry ,medicine.disease ,030104 developmental biology ,Mutation ,Cancer research ,business ,Transforming growth factor - Abstract
Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling., The therapies for bone metastatic prostate cancer are limited and the underlying mechanisms are unclear. Here, the authors show that bone derived TGF-β induces acetylation of KLF5 (Ac-KLF5), and Ac-KLF5 promotes prostate cancer bone metastasis and resistance to docetaxel by upregulating CXCR4.
- Published
- 2021
46. CD8 T Cell Activation in Cancer is Comprised of Two Distinct Phases
- Author
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Rajesh M. Valanparambil, Maria A. Cardenas, Cara B. Cimmino, Benjamin G. Barwick, Rachel Greenwald, Haydn T. Kissick, Nataliya Prokhnevska, Mehrdad Alemozaffar, Martin G. Sanda, Petra Gregorova, Adriana R. Moon, Ewelina Sobierajska, Caroline S. Jansen, Christian Albrekt Larsen, Luke delBalzo, Viraj A. Master, and Mehmet Asim Bilen
- Subjects
Chemistry ,Cancer research ,medicine ,Cytotoxic T cell ,Cancer ,medicine.disease - Published
- 2021
47. Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma
- Author
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Jonathan L. Kaufman, Craig C. Hofmeister, Yanyan Gu, Ajay K. Nooka, Benjamin G. Barwick, Lawrence H. Boise, Mala Shanmugam, Vikas Gupta, Sagar Lonial, and Madhav V. Dhodapkar
- Subjects
0301 basic medicine ,Proteasome Endopeptidase Complex ,Down-Regulation ,Muscle Proteins ,Myeloma ,Plasma cell ,lcsh:RC254-282 ,Article ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Humans ,Multiple myeloma ,Eukaryotic cell ,biology ,Chemistry ,Activator (genetics) ,Hematology ,Translational research ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Cell biology ,Gene Expression Regulation, Neoplastic ,Protein catabolism ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Proteasome ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,Multiple Myeloma ,Proteasome Inhibitors - Abstract
Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.
- Published
- 2020
48. We need CD38 STAT-JAK
- Author
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Benjamin G. Barwick and Sagar Lonial
- Subjects
Lymphoid Neoplasia ,business.industry ,Immunology ,MEDLINE ,hemic and immune systems ,Cell Count ,Cell Biology ,Hematology ,CD38 ,Biochemistry ,stat ,STAT Transcription Factors ,immune system diseases ,Bone Marrow ,hemic and lymphatic diseases ,Cancer research ,Medicine ,Humans ,business ,Multiple Myeloma ,Janus Kinases - Abstract
Anti-CD38 monoclonal antibody (MoAb) treatments including daratumumab (DARA) are effective therapies for both newly diagnosed and relapsed multiple myeloma (MM). In this study, we examined the soluble factors that modulate CD38 expression and are associated with sensitivity to DARA-mediated antibody-dependent cellular cytotoxicity (ADCC) in the bone marrow (BM) microenvironment. Importantly, primary BM stromal cell (BMSC) culture supernatant (BMSC-sup) and interleukin-6 (IL-6) downregulated CD38 expression and reduced DARA-mediated ADCC. Both cytokine profiling of the BMSC-sup and genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) knockout screening in MM cell lines identified and validated the JAK-STAT3 signaling pathway mediating CD38 downregulation, whereas the JAK-STAT1 pathway mediated CD38 upregulation. STAT3 knockdown abrogated BMSC-sup– and IL-6–induced CD38 downregulation on MM cell lines. We also confirmed that STAT3 and CD38 is negatively correlated in primary MM cells. To assess potential clinical relevance, pharmacological inhibition of the JAK-STAT pathway on BMSC-sup–induced CD38 downregulation was further examined. JAK inhibitor ruxolitinib inhibited STAT3 phosphorylation in MM cell lines, upregulated CD38 expression in MM cell lines and primary patient MM cells, and augmented DARA-mediated ADCC against MM cell lines. Taken together, our results suggest that CD38 expression on MM cells in the BM microenvironment is regulated by both STAT1 (positively) and STAT3 (negatively), and that inhibition of the JAK-STAT3 pathway represents a novel therapeutic option to enhance CD38 expression and anti-CD38 MoAb-mediated MM cytotoxicity.
- Published
- 2020
49. YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell-Inflamed Phenotype
- Author
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Gabriel Sica, Chao Zhang, Jennifer W Carlisle, Shi-Yong Sun, Edmund K. Waller, Guojing Zhang, Vinicius Ernani, Taofeek K. Owonikoko, Zhengjia Chen, Walter J. Curran, Bhakti Dwivedi, Benjamin G. Barwick, Melissa Gilbert-Ross, Fadlo R. Khuri, Andrey A. Ivanov, Haian Fu, Suresh S. Ramalingam, and Sagar Lonial
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,T-Lymphocytes ,Human leukocyte antigen ,Neuroendocrine tumors ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Gene expression ,medicine ,Humans ,Gene ,neoplasms ,YAP1 ,business.industry ,medicine.disease ,Phenotype ,Small Cell Lung Carcinoma ,humanities ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Biomarker (medicine) ,business - Abstract
Introduction The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established. Methods We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples. Results We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene set enrichment analysis for differentially expressed genes between the SCLC survival outliers (top and bottom deciles) matched for clinically relevant prognostic factors revealed substantial up-regulation of interferon-γ response genes in long-term survivors. The SCLC-Y subtype was associated with high expression of interferon-γ response genes, highest weighted score on a validated 18-gene T-cell–inflamed gene expression profile score, and high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited-stage versus extensive-stage SCLC (30.6% versus 8.5%; p = 0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation data sets from the SCLC cell lines and tumor samples. Conclusions SCLC subtyping using transcriptional signaling holds clinical relevance with the inflamed phenotype associated with the SCLC-Y subset.
- Published
- 2020
50. Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning
- Author
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Benjamin G. Barwick, Jamie L. Arnst, Joshua S.K. Bell, Jeanne Kowalski, Brian Pedro, Sandra Seby, Jessica Konen, Bhakti Dwivedi, Adam I. Marcus, Rachel Commander, Paula M. Vertino, Tala O. Khatib, Christina M. Knippler, Janna K. Mouw, and Emily R. Summerbell
- Subjects
JAG1 ,animal structures ,macromolecular substances ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,medicine ,Epigenetics ,Research Articles ,Cancer ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,SciAdv r-articles ,Cell Biology ,medicine.disease ,Cell biology ,Fibronectin ,030220 oncology & carcinogenesis ,DNA methylation ,biology.protein ,Filopodia ,Research Article ,Micropatterning - Abstract
Specialized leader cells use stable filopodia to create linear fibronectin tracks to promote collective cancer invasion., Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor MYO10 as a critical gene at the intersection of epigenetic heterogeneity and three-dimensional (3D) collective invasion. We further identified JAG1 signaling as a previously unknown upstream activator of MYO10 expression in leader cells. Using live-cell imaging, we found that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1 signaling jointly drive collective cancer invasion through MYO10 up-regulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning.
- Published
- 2020
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