693 results on '"Mayakonda, A"'
Search Results
2. Bovine HDL and Dual Domain HDL-Mimetic Peptides Inhibit Tumor Development in Mice.
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Su, Feng, Gm, Anantharamaiah, Palgunachari, Mayakonda N, White, C Roger, Stessman, Holly, Wu, Yanyuan, Vadgama, Jay, Pietras, Richard, Nguyen, Dorothy, Reddy, Srinivasa T, and Farias-Eisner, Robin
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Cancer Therapeutics ,Colon Cancer ,HDL ,LPA ,Mimetic Peptides ,Ovarian Cancer - Abstract
A growing body of literature supports the role of apolipoproteins present in HDL in the treatment of pro-inflammatory diseases including cancer. We examined whether bovine HDL (bHDL) and three dual-domain peptides, namely AEM-28 and its analog AEM-28-2, and HM-10/10, affect tumor growth and development in mouse models of ovarian and colon cancer. We demonstrate that bHDL inhibits mouse colorectal cancer cell line CT26-mediated lung tumor development, and mouse ovarian cancer cell line ID8-mediated tumor burden. We also demonstrate that, although to different degrees, dual-domain peptides inhibit cell viability of mouse and human ovarian and colon cancer cell lines, but not that of normal human colonic epithelial cells or NIH3T3 mouse fibroblasts. Dual-domain peptides administered subcutaneously or in a chow diet decrease CT26 cell-mediated tumor burden, tumor growth, and tumor dissemination in BALB/c mice. Plasma levels of lysophosphatidic acid (LPA) are significantly reduced in mice that received bHDL and the dual-domain peptides, suggesting that reduction by effecting accumulation and/or synthesis of pro-inflammatory lipids may be one of the mechanisms for the inhibition of tumor development by bHDL and the dual-domain peptides. Our studies suggest that therapeutics based on apolipoproteins present in HDL may be novel agents for the treatment of epithelial adenocarcinomas of the ovary and colon.
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- 2020
3. Apolipoprotein A-I mimetics mitigate intestinal inflammation in COX2-dependent inflammatory bowel disease model
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Meriwether, David, Sulaiman, Dawoud, Volpe, Carmen, Dorfman, Anna, Grijalva, Victor, Dorreh, Nasrin, Solorzano-Vargas, R Sergio, Wang, Jifang, O'Connor, Ellen, Papesh, Jeremy, Larauche, Muriel, Trost, Hannah, Palgunachari, Mayakonda N, Anantharamaiah, GM, Herschman, Harvey R, Martin, Martin G, Fogelman, Alan M, and Reddy, Srinivasa T
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Autoimmune Disease ,Crohn's Disease ,Biotechnology ,Digestive Diseases ,Inflammatory Bowel Disease ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Oral and gastrointestinal ,Inflammatory and immune system ,Animals ,Apolipoprotein A-I ,Cyclooxygenase 2 ,Disease Models ,Animal ,Endotoxins ,Female ,Humans ,Inflammatory Bowel Diseases ,Intestines ,Macrophages ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Oxygen ,Peptides ,Permeability ,Piroxicam ,Receptors ,Formyl Peptide ,Signal Transduction ,Eicosanoids ,Gastroenterology ,Inflammatory bowel disease ,Lipoproteins ,Medical and Health Sciences ,Immunology - Abstract
Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2 KO but not WT mice. Cox2 MKO increased pro-inflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2 MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, while administration of an LXA4 analog rescued disease in Cox2 MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2 MKO/CCHF and piroxicam-accelerated Il10-/- models of inflammatory bowel disease (IBD) and reduced elevated levels of pro-inflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2 MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides: i) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (oxPAPC) dependent pro-inflammatory responses in human macrophages and intestinal epithelium; and ii) directly cleared pro-inflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for pro-inflammatory and inflammation resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.
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- 2019
4. Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice.
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Han, Lin, Madan, Vikas, Mayakonda, Anand, Dakle, Pushkar, Woon, Teoh, Shyamsunder, Pavithra, Nordin, Hazimah, Cao, Zeya, Sundaresan, Janani, Lei, Ienglam, Wang, Zhong, and Koeffler, H
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Animals ,Cell Differentiation ,Cell Line ,Tumor ,Cell Lineage ,Chromatin ,Chromatin Assembly and Disassembly ,DNA-Binding Proteins ,Hematopoiesis ,Humans ,Mice ,Mice ,Inbred C57BL ,Myeloid Cells ,Transcription Factors - Abstract
Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice. We demonstrate that ARID1A is essential for maintaining the frequency and function of hematopoietic stem cells and its loss impairs the differentiation of both myeloid and lymphoid lineages. ARID1A deficiency led to a global reduction in open chromatin and ensuing transcriptional changes affected key genes involved in hematopoietic development. We also observed that silencing of ARID1A affected ATRA-induced differentiation of NB4 cells, suggesting its role in granulocytic differentiation of human leukemic cells. Overall, our study provides a comprehensive elucidation of the function of ARID1A in hematopoiesis and highlights the central role of ARID1A-containing SWI/SNF complex in maintaining chromatin dynamics in hematopoietic cells.
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- 2019
5. Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma.
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Chen, Ye, Xu, Liang, Mayakonda, Anand, Huang, Mo-Li, Kanojia, Deepika, Tan, Tuan Zea, Dakle, Pushkar, Lin, Ruby Yu-Tong, Ke, Xin-Yu, Said, Jonathan W, Chen, Jianxiang, Gery, Sigal, Ding, Ling-Wen, Jiang, Yan-Yi, Pang, Angela, Puhaindran, Mark Edward, Goh, Boon Cher, and Koeffler, H Phillip
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Cell Line ,Tumor ,Animals ,Mice ,Inbred NOD ,Humans ,Mice ,SCID ,Liposarcoma ,Thalidomide ,Azepines ,Neoplasm Proteins ,Oncogene Proteins ,Fusion ,Transcription ,Genetic ,Base Sequence ,Genome ,Human ,Enhancer Elements ,Genetic ,Carcinogenesis ,Cell Line ,Tumor ,Enhancer Elements ,Genetic ,Genome ,Human ,Mice ,Inbred NOD ,SCID ,Oncogene Proteins ,Fusion ,Transcription - Abstract
Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.
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- 2019
6. Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1
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Lin, Lehang, Huang, Moli, Shi, Xianping, Mayakonda, Anand, Hu, Kaishun, Jiang, Yan-Yi, Guo, Xiao, Chen, Li, Pang, Brendan, Doan, Ngan, Said, Jonathan W, Xie, Jianjun, Gery, Sigal, Cheng, Xu, Lin, Zhaoyu, Li, Jinsong, Berman, Benjamin P, Yin, Dong, Lin, De-Chen, and Koeffler, H Phillip
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Biotechnology ,Pediatric Cancer ,Genetics ,Pediatric ,Pediatric Research Initiative ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Apoptosis ,Cell Line ,Tumor ,Cell Proliferation ,Enhancer Elements ,Genetic ,Gene Expression Regulation ,Neoplastic ,Humans ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Nucleotide Motifs ,Oncogene Proteins ,Fusion ,Proto-Oncogene Protein c-fli-1 ,RNA-Binding Protein EWS ,Sarcoma ,Ewing ,Signal Transduction ,Transcription ,Genetic ,Environmental Sciences ,Biological Sciences ,Information and Computing Sciences ,Developmental Biology - Abstract
As the second most common malignant bone tumor in children and adolescents, Ewing sarcoma is initiated and exacerbated by a chimeric oncoprotein, most commonly, EWS-FLI1. In this study, we apply epigenomic analysis to characterize the transcription dysregulation in this cancer, focusing on the investigation of super-enhancer and its associated transcriptional regulatory mechanisms. We demonstrate that super-enhancer-associated transcripts are significantly enriched in EWS-FLI1 target genes, contribute to the aberrant transcriptional network of the disease, and mediate the exceptional sensitivity of Ewing sarcoma to transcriptional inhibition. Through integrative analysis, we identify MEIS1 as a super-enhancer-driven oncogene, which co-operates with EWS-FLI1 in transcriptional regulation, and plays a key pro-survival role in Ewing sarcoma. Moreover, APCDD1, another super-enhancer-associated gene, acting as a downstream target of both MEIS1 and EWS-FLI1, is also characterized as a novel tumor-promoting factor in this malignancy. These data delineate super-enhancer-mediated transcriptional deregulation in Ewing sarcoma, and uncover numerous candidate oncogenes which can be exploited for further understanding of the molecular pathogenesis for this disease.
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- 2019
7. Profiling the B/T cell receptor repertoire of lymphocyte derived cell lines
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Tan, Kar-Tong, Ding, Ling-Wen, Sun, Qiao-Yang, Lao, Zhen-Tang, Chien, Wenwen, Ren, Xi, Xiao, Jin-Fen, Loh, Xin Yi, Xu, Liang, Lill, Michael, Mayakonda, Anand, Lin, De-Chen, Yang, Henry, and Koeffler, H Phillip
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Rare Diseases ,Lymphoma ,Hematology ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,B-Lymphocytes ,Cell Line ,Tumor ,Hematologic Neoplasms ,Herpesvirus 4 ,Human ,Humans ,Lymphocytes ,Neoplasms ,RNA ,Receptors ,Antigen ,B-Cell ,Receptors ,Antigen ,T-Cell ,BCR/TCR receptor repertoire ,EBV lymphocytes ,Cancer cell lines ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Epidemiology - Abstract
BackgroundClonal VDJ rearrangement of B/T cell receptors (B/TCRs) occurring during B/T lymphocyte development has been used as a marker to track the clonality of B/T cell populations.MethodsWe systematically profiled the B/T cell receptor repertoire of 936 cancer cell lines across a variety of cancer types as well as 462 Epstein-Barr Virus (EBV) transformed normal B lymphocyte lines using RNA sequencing data.ResultsRearranged B/TCRs were readily detected in cell lines derived from lymphocytes, and subclonality or potential biclonality were found in a number of blood cancer cell lines. Clonal BCR/TCR rearrangements were detected in several blast phase CML lines and unexpectedly, one gastric cancer cell line (KE-97), reflecting a lymphoid origin of these cells. Notably, clonality was highly prevalent in EBV transformed B lymphocytes, suggesting either transformation only occurred in a few B cells or those with a growth advantage dominated the transformed population through clonal evolution.ConclusionsOur analysis reveals the complexity and heterogeneity of the BCR/TCR rearrangement repertoire and provides a unique insight into the clonality of lymphocyte derived cell lines.
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- 2018
8. ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
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Madan, Vikas, Han, Lin, Hattori, Norimichi, Teoh, Weoi Woon, Mayakonda, Anand, Sun, Qiao-Yang, Ding, Ling-Wen, Nordin, Hazimah Binte Mohd, Lim, Su Lin, Shyamsunder, Pavithra, Dakle, Pushkar, Sundaresan, Janani, Doan, Ngan B, Sanada, Masashi, Sato-Otsubo, Aiko, Meggendorfer, Manja, Yang, Henry, Said, Jonathan W, Ogawa, Seishi, Haferlach, Torsten, Liang, Der-Cherng, Shih, Lee-Yung, Nakamaki, Tsuyoshi, Wang, Q Tian, and Koeffler, H Phillip
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Rare Diseases ,Human Genome ,Childhood Leukemia ,Cancer ,Pediatric ,Hematology ,Pediatric Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Acute Disease ,Animals ,Cell Differentiation ,Cell Proliferation ,Gene Expression Profiling ,Hematopoiesis ,Humans ,Leukemia ,Myeloid ,Mice ,129 Strain ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myeloid Cells ,Myelopoiesis ,Repressor Proteins ,Immunology - Abstract
Chromosomal translocation t(8;21)(q22;q22) which leads to the generation of oncogenic RUNX1-RUNX1T1 (AML1-ETO) fusion is observed in approximately 10% of acute myelogenous leukemia (AML). To identify somatic mutations that co-operate with t(8;21)-driven leukemia, we performed whole and targeted exome sequencing of an Asian cohort at diagnosis and relapse. We identified high frequency of truncating alterations in ASXL2 along with recurrent mutations of KIT, TET2, MGA, FLT3, and DHX15 in this subtype of AML. To investigate in depth the role of ASXL2 in normal hematopoiesis, we utilized a mouse model of ASXL2 deficiency. Loss of ASXL2 caused progressive hematopoietic defects characterized by myeloid hyperplasia, splenomegaly, extramedullary hematopoiesis, and poor reconstitution ability in transplantation models. Parallel analyses of young and >1-year old Asxl2-deficient mice revealed age-dependent perturbations affecting, not only myeloid and erythroid differentiation, but also maturation of lymphoid cells. Overall, these findings establish a critical role for ASXL2 in maintaining steady state hematopoiesis, and provide insights into how its loss primes the expansion of myeloid cells.
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- 2018
9. TAL1 activation in T-cell acute lymphoblastic leukemia: a novel oncogenic 3’ neo-enhancer
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Charlotte Smith, Ashish Goyal, Dieter Weichenhan, Eric Allemand, Anand Mayakonda, Umut Toprak, Anna Riedel, Estelle Balducci, Manisha Manojkumar, Anastasija Pejkovska, Oliver Mücke, Etienne Sollier, Ali Bakr, Kersten Breuer, Pavlo Lutsik, Olivier Hermine, Salvatore Spicuglia, Vahid Asnafi, Christoph Plass, and Aurore Touzart
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse cis-alterations, including SIL-TAL1 microdeletions, translocations with T-cell Receptor loci, and more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied by activating epigenetic marks. This observation laid the groundwork for an innovative paradigm concerning the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of T-ALL expressing TAL1 (TAL1+), the deregulation mechanism remains 'unresolved'. We took advantage of H3K27ac and H3K4me3 chromatin immunoprecipitation sequencing data of eight cases of T-ALL, including five TAL1+ cases. We identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an unresolved monoallelic TAL1+ case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor. Here we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks, and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.
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- 2023
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10. Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma
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Xu, Liang, Chen, Ye, Mayakonda, Anand, Koh, Lynnette, Chong, Yuk Kien, Buckley, Dennis L, Sandanaraj, Edwin, Lim, See Wee, Lin, Ruby Yu-Tong, Ke, Xin-Yu, Huang, Mo-Li, Chen, Jianxiang, Sun, Wendi, Wang, Ling-Zhi, Goh, Boon Cher, Dinh, Huy Q, Kappei, Dennis, Winter, Georg E, Ding, Ling-Wen, Ang, Beng Ti, Berman, Benjamin P, Bradner, James E, Tang, Carol, and Koeffler, H Phillip
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Brain Disorders ,Genetics ,Cancer ,Neurosciences ,Rare Diseases ,Brain Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Antineoplastic Agents ,Cell Cycle Proteins ,Cell Line ,Tumor ,Drug Delivery Systems ,E2F1 Transcription Factor ,Gene Expression Regulation ,Neoplastic ,Glioblastoma ,Humans ,Nuclear Proteins ,Protein Domains ,Protein Serine-Threonine Kinases ,RNA-Binding Proteins ,Transcription Factors ,glioma ,BRD2 ,BRD3 ,BRD4 ,E2F - Abstract
Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.
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- 2018
11. Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma
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Yuan, Jiang, Jiang, Yan-Yi, Mayakonda, Anand, Huang, Moli, Ding, Ling-Wen, Lin, Han, Yu, Fenggang, Lu, Yanan, Loh, Thomas Kwok Seng, Chow, Marilynn, Savage, Samantha, Tyner, Jeffrey W, Lin, De-Chen, and Koeffler, H Phillip
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Genetics ,Human Genome ,Biotechnology ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Antineoplastic Agents ,Carcinoma ,Cell Line ,Tumor ,Chromatin Immunoprecipitation ,Cyclin-Dependent Kinases ,DNA-Binding Proteins ,Gene Expression Regulation ,Neoplastic ,HEK293 Cells ,Humans ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Nasopharyngeal Carcinoma ,Nasopharyngeal Neoplasms ,Phenylenediamines ,Proto-Oncogene Protein c-ets-2 ,Pyrimidines ,RNA ,Long Noncoding ,Transcription ,Genetic ,Xenograft Model Antitumor Assays ,Cyclin-Dependent Kinase-Activating Kinase ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced antineoplastic activities both in vitro and in vivo An integrative analysis using both whole-transcriptome sequencing and chromatin immunoprecipitation sequencing pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2, and the long noncoding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK, and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease. Cancer Res; 77(23); 6614-26. ©2017 AACR.
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- 2017
12. Mutational profiling of acute lymphoblastic leukemia with testicular relapse
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Ding, Ling-Wen, Sun, Qiao-Yang, Mayakonda, Anand, Tan, Kar-Tong, Chien, Wenwen, Lin, De-Chen, Jiang, Yan-Yi, Xu, Liang, Garg, Manoj, Lao, Zhen-Tang, Lill, Michael, Yang, Henry, Yeoh, Allen Eng Juh, and Koeffler, H Phillip
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Oncology and Carcinogenesis ,Clinical Research ,Urologic Diseases ,Childhood Leukemia ,Genetics ,Pediatric Research Initiative ,Pediatric Cancer ,Pediatric ,Cancer ,Rare Diseases ,Hematology ,Human Genome ,Biotechnology ,Child ,Preschool ,Clonal Evolution ,DNA Mutational Analysis ,Humans ,Infant ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Recurrence ,Testicular Neoplasms ,Acute lymphoblastic leukemia ,ALL ,Testicular relapse ,Extramedullary relapse ,Cardiorespiratory Medicine and Haematology ,Cardiovascular medicine and haematology ,Oncology and carcinogenesis - Abstract
Relapsed acute lymphoblastic leukemia (ALL) is the leading cause of deaths of childhood cancer. Although relapse usually happens in the bone marrow, extramedullary relapse occasionally occurs including either the central nervous system or testis (
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- 2017
13. Peptides as Therapeutic Agents for Atherosclerosis
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White, C. Roger, primary, Palgunachari, Mayakonda, additional, Wolkowicz, Paul, additional, and Anantharamaiah, G. M., additional
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- 2022
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14. Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin.
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Garg, Manoj, Kanojia, Deepika, Mayakonda, Anand, Ganesan, Trivadi S, Sadhanandhan, Bindhya, Suresh, Sidhanth, S, Sneha, Nagare, Rohit P, Said, Jonathan W, Doan, Ngan B, Ding, Ling-Wen, Baloglu, Erkan, Shacham, Sharon, Kauffman, Michael, and Koeffler, H Phillip
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Tumor Cells ,Cultured ,Animals ,Humans ,Thyroid Neoplasms ,Disease Models ,Animal ,Hydrazines ,Triazoles ,Doxorubicin ,Karyopherins ,Receptors ,Cytoplasmic and Nuclear ,Antineoplastic Agents ,Treatment Outcome ,Neoplasm Transplantation ,Apoptosis ,Models ,Biological ,Cell Cycle Checkpoints ,Heterografts ,Thyroid Carcinoma ,Anaplastic ,Tumor Cells ,Cultured ,Disease Models ,Animal ,Receptors ,Cytoplasmic and Nuclear ,Models ,Biological ,Thyroid Carcinoma ,Anaplastic - Abstract
Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies having no effective treatment. Exportin-1 (XPO1) is the key mediator of nuclear export of many tumor suppressor proteins and is overexpressed in human cancers. In this study, we examined the therapeutic potential of selinexor (XPO1 inhibitor) against human ATC cells both in vitro and in vivo. Here, we showed that XPO1 is robustly expressed in primary ATC samples and human ATC cell lines. Silencing of XPO1 by either shRNA or selinexor significantly reduced cellular growth and induced cell cycle arrest, apoptosis of ATC cells by altering the protein expression of cancer-related genes. Moreover, selinexor significantly inhibited tumor growth of ATC xenografts. Microarray analysis showed enrichment of DNA replication, cell cycle, cell cycle checkpoint and TNF pathways in selinexor treated ATC cells. Importantly, selinexor decreased AXL and GAS6 levels in CAL62 and HTH83 cells and suppressed the phosphorylation of downstream targets of AXL signaling such as AKT and P70S6K. Finally, a combination of selinexor with doxorubicin demonstrated a synergistic decrease in the cellular proliferation of several ATC cells. These results provide a rationale for investigating the efficacy of combining selinexor and doxorubicin therapy to improve the outcome of ATC patients.
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- 2017
15. Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma
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Jiang, Yan-Yi, Lin, De-Chen, Mayakonda, Anand, Hazawa, Masaharu, Ding, Ling-Wen, Chien, Wen-Wen, Xu, Liang, Chen, Ye, Xiao, Jin-Fen, Senapedis, William, Baloglu, Erkan, Kanojia, Deepika, Shang, Li, Xu, Xin, Yang, Henry, Tyner, Jeffrey W, Wang, Ming-Rong, and Koeffler, H Phillip
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,Human Genome ,Rare Diseases ,Cancer ,Genetics ,Biotechnology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Aetiology ,Development of treatments and therapeutic interventions ,Acrylamides ,Adaptor Proteins ,Signal Transducing ,Aminopyridines ,Animals ,Antineoplastic Agents ,Carcinoma ,Squamous Cell ,Cell Line ,Tumor ,Cell Proliferation ,Core Binding Factor Alpha 2 Subunit ,Cyclin-Dependent Kinases ,Drug Screening Assays ,Antitumor ,Esophageal Neoplasms ,Female ,Gene Expression ,Gene Expression Profiling ,HSP40 Heat-Shock Proteins ,High-Throughput Screening Assays ,Humans ,Mice ,Neoplasm Transplantation ,Oncogenes ,Phenylenediamines ,Phosphoproteins ,Pyrimidines ,Sequence Analysis ,RNA ,Sterol Regulatory Element Binding Protein 2 ,Transcription Factors ,Transcriptome ,YAP-Signaling Proteins ,p21-Activated Kinases ,Cyclin-Dependent Kinase-Activating Kinase ,CANCER ,CELL BIOLOGY ,OESOPHAGEAL CANCER ,ONCOGENES ,Clinical Sciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
ObjectivesOesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour.DesignHigh-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes.ResultsThe unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase.ConclusionsOur integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies.
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- 2017
16. Correction for Xu et al., BCL6 promotes glioma and serves as a therapeutic target
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Xu, Liang, Chen, Ye, Dutra-Clarke, Marina, Mayakonda, Anand, Hazawa, Masaharu, Savinoff, Steve E, Ngan, Doan, Said, Jonathan W, Yong, William H, Watkins, Ashley, Yang, Henry, Ding, Ling-Wen, Jiang, Yan-Yi, Tyner, Jeffrey W, Ching, Jianhong, Kovalik, Jean-Paul, Madan, Vikas, Chan, Shing-Leng, Muschen, Markus, Breunig, Joshua J, Lin, De-Chen, and Koeffler, H Phillip
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- 2017
17. Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma
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Lin, De-Chen, Mayakonda, Anand, Dinh, Huy Q, Huang, Pinbo, Lin, Lehang, Liu, Xiaoping, Ding, Ling-Wen, Wang, Jie, Berman, Benjamin P, Song, Er-Wei, Yin, Dong, and Koeffler, H Phillip
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Human Genome ,Genetics ,Biotechnology ,Liver Cancer ,Digestive Diseases ,Cancer ,Rare Diseases ,Liver Disease ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adult ,Aged ,Carcinoma ,Hepatocellular ,DNA Copy Number Variations ,DNA Mutational Analysis ,Exome ,Female ,Genetic Heterogeneity ,Genomics ,High-Throughput Nucleotide Sequencing ,Humans ,Liver Neoplasms ,Male ,Middle Aged ,Mutation ,Neoplasm Proteins ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 hepatocellular carcinoma cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions, that is, located on the "trunk" of the evolutionary tree. In addition, we found that variants within several drug targets such as KIT, SYK, and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for hepatocellular carcinoma. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of hepatocellular carcinoma development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in hepatocellular carcinoma based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of hepatocellular carcinoma cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable hepatocellular carcinoma genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in hepatocellular carcinoma and provide an important molecular foundation for better understanding the pathogenesis of this malignancy. Cancer Res; 77(9); 2255-65. ©2017 AACR.
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- 2017
18. BCL6 promotes glioma and serves as a therapeutic target.
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Xu, Liang, Chen, Ye, Dutra-Clarke, Marina, Mayakonda, Anand, Hazawa, Masaharu, Savinoff, Steve E, Doan, Ngan, Said, Jonathan W, Yong, William H, Watkins, Ashley, Yang, Henry, Ding, Ling-Wen, Jiang, Yan-Yi, Tyner, Jeffrey W, Ching, Jianhong, Kovalik, Jean-Paul, Madan, Vikas, Chan, Shing-Leng, Müschen, Markus, Breunig, Joshua J, Lin, De-Chen, and Koeffler, H Phillip
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Mutant Strains ,Glioma ,Glioblastoma ,Brain Neoplasms ,Quinazolines ,MAP Kinase Kinase Kinases ,Receptor Protein-Tyrosine Kinases ,Proto-Oncogene Proteins ,Xenograft Model Antitumor Assays ,Signal Transduction ,Gene Expression Regulation ,Neoplastic ,Tumor Suppressor Protein p53 ,Proto-Oncogene Proteins c-bcl-6 ,Molecular Targeted Therapy ,Gefitinib ,Axl Receptor Tyrosine Kinase ,AXL ,BCL6 ,NCoR ,ZBTB ,glioblastoma multiforme ,Cancer ,Brain Cancer ,Brain Disorders ,Biotechnology ,Neurosciences ,Genetics ,Rare Diseases - Abstract
ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.
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- 2017
19. ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma
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Hazawa, M, Lin, D-C, Handral, H, Xu, L, Chen, Y, Jiang, Y-Y, Mayakonda, A, Ding, L-W, Meng, X, Sharma, A, Samuel, S, Movahednia, MM, Wong, RW, Yang, H, Tong, C, and Koeffler, HP
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Cancer ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Carcinoma ,Squamous Cell ,Cell Differentiation ,Cell Line ,Tumor ,Cell Lineage ,Cell Movement ,DNA ,Neoplasm ,Esophageal Neoplasms ,Female ,Gene Deletion ,Gene Expression Regulation ,Neoplastic ,Genes ,Tumor Suppressor ,HEK293 Cells ,Head and Neck Neoplasms ,Humans ,Laminin ,Mice ,Mice ,Inbred NOD ,Mutation ,Oligonucleotide Array Sequence Analysis ,Prognosis ,RNA ,Long Noncoding ,Transcription Factors ,Transcriptome ,Tumor Suppressor Proteins ,Uterine Cervical Neoplasms ,Clinical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
ZNF750 controls epithelial homeostasis by regulating epidermal-differentiation genes, a role underscored by its pathogenic mutations in esophageal squamous cell cancers (SCCs). However, the precise role of ZNF750 in SCC cell biology remains unclear. In this study, we report that ZNF750 is exclusively deleted, mutated and underexpressed in human SCCs, and low ZNF750 expression is associated with poor survival. Restoration of wildtype, but not mutant ZNF750 protein uniquely inhibited the malignant phenotypes of SCC cells both in vitro and in vivo. Notably, ZNF750 promoted the expression of a long non-coding RNA (TINCR), which mediated both cancer-inhibition and differentiation-induction effects of ZNF750. In addition, ZNF750 potently suppressed cell migration by directly inhibiting the transactivation of LAMC2. Together, our findings characterize ZNF750 as a crucial SCC-specific suppressor and uncover its novel anticancer-associated functions.
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- 2017
20. Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma
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Garg, Manoj, Kanojia, Deepika, Mayakonda, Anand, Said, Jonathan W, Doan, Ngan B, Chien, Wenwen, Ganesan, Trivadi S, Chuang, Linda Shyue Huey, Venkatachalam, Nachiyappan, Baloglu, Erkan, Shacham, Sharon, Kauffman, Michael, and Koeffler, H Phillip
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biotechnology ,Cancer ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Aetiology ,Development of treatments and therapeutic interventions ,Animals ,Antineoplastic Agents ,Apoptosis ,Aurora Kinase A ,Aurora Kinase B ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,Cell Proliferation ,Dose-Response Relationship ,Drug ,Gene Expression Regulation ,Neoplastic ,Humans ,Hydrazines ,Insulin-Like Growth Factor Binding Protein 5 ,Karyopherins ,Liposarcoma ,Male ,Mice ,Proto-Oncogene Proteins c-akt ,RNA Interference ,Receptor ,IGF Type 1 ,Receptors ,Cytoplasmic and Nuclear ,Receptors ,Somatomedin ,Signal Transduction ,Time Factors ,Transfection ,Triazoles ,Tumor Burden ,Xenograft Model Antitumor Assays ,selinexor ,IGFBP5 ,xenograft ,cell cycle ,Oncology and carcinogenesis - Abstract
Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.
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- 2017
21. Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
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Ding, Ling-Wen, Sun, Qiao-Yang, Tan, Kar-Tong, Chien, Wenwen, Thippeswamy, Anand Mayakonda, Yeoh, Allen Eng Juh, Kawamata, Norihiko, Nagata, Yasunobu, Xiao, Jin-Fen, Loh, Xin-Yi, Lin, De-Chen, Garg, Manoj, Jiang, Yan-Yi, Xu, Liang, Lim, Su-Lin, Liu, Li-Zhen, Madan, Vikas, Sanada, Masashi, Fernández, Lucia Torres, Preethi, Hema, Lill, Michael, Kantarjian, Hagop M, Kornblau, Steven M, Miyano, Satoru, Liang, Der-Cherng, Ogawa, Seishi, Shih, Lee-Yung, Yang, Henry, and Koeffler, H Phillip
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Clinical Research ,Childhood Leukemia ,Pediatric Research Initiative ,Pediatric Cancer ,Biotechnology ,Hematology ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adolescent ,Animals ,Blotting ,Western ,Child ,Child ,Preschool ,DNA Mutational Analysis ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Infant ,Male ,Mice ,Mutation ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390-400. ©2016 AACR.
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- 2017
22. Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD)
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Sun, Q-Y, Ding, L-W, Tan, K-T, Chien, W, Mayakonda, A, Lin, D-C, Loh, X-Y, Xiao, J-F, Meggendorfer, M, Alpermann, T, Garg, M, Lim, S-L, Madan, V, Hattori, N, Nagata, Y, Miyano, S, Yeoh, AEJ, Hou, H-A, Jiang, Y-Y, Takao, S, Liu, L-Z, Tan, S-Z, Lill, M, Hayashi, M, Kinoshita, A, Kantarjian, HM, Kornblau, SM, Ogawa, S, Haferlach, T, Yang, H, and Koeffler, HP
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Cancer ,Childhood Leukemia ,Pediatric ,Genetics ,Pediatric Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Cell Proliferation ,Clone Cells ,Exome ,Histone-Lysine N-Methyltransferase ,Humans ,Leukemia ,Myeloid ,Acute ,Mutation ,Mutation Rate ,Myeloid-Lymphoid Leukemia Protein ,Nucleophosmin ,Tandem Repeat Sequences ,Time Factors ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.
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- 2017
23. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma
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Hao, Jia-Jie, Lin, De-Chen, Dinh, Huy Q, Mayakonda, Anand, Jiang, Yan-Yi, Chang, Chen, Jiang, Ye, Lu, Chen-Chen, Shi, Zhi-Zhou, Xu, Xin, Zhang, Yu, Cai, Yan, Wang, Jin-Wu, Zhan, Qi-Min, Wei, Wen-Qiang, Berman, Benjamin P, Wang, Ming-Rong, and Koeffler, H Phillip
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Agricultural ,Veterinary and Food Sciences ,Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Agricultural Biotechnology ,Clinical Research ,Rare Diseases ,Human Genome ,Digestive Diseases ,Biotechnology ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Carcinoma ,Squamous Cell ,Clonal Evolution ,Clone Cells ,Cohort Studies ,DNA Methylation ,Esophageal Neoplasms ,Exome ,Gene Expression Regulation ,Neoplastic ,High-Throughput Nucleotide Sequencing ,Humans ,Mutation ,Neoplasm Proteins ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC.
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- 2016
24. Trackplot: a fast and lightweight R script for epigenomic enrichment plots
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Mayakonda, Anand, primary and Westermann, Frank, additional
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- 2024
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25. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia
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Madan, V, Shyamsunder, P, Han, L, Mayakonda, A, Nagata, Y, Sundaresan, J, Kanojia, D, Yoshida, K, Ganesan, S, Hattori, N, Fulton, N, Tan, K-T, Alpermann, T, Kuo, M-C, Rostami, S, Matthews, J, Sanada, M, Liu, L-Z, Shiraishi, Y, Miyano, S, Chendamarai, E, Hou, H-A, Malnassy, G, Ma, T, Garg, M, Ding, L-W, Sun, Q-Y, Chien, W, Ikezoe, T, Lill, M, Biondi, A, Larson, RA, Powell, BL, Lübbert, M, Chng, WJ, Tien, H-F, Heuser, M, Ganser, A, Koren-Michowitz, M, Kornblau, SM, Kantarjian, HM, Nowak, D, Hofmann, W-K, Yang, H, Stock, W, Ghavamzadeh, A, Alimoghaddam, K, Haferlach, T, Ogawa, S, Shih, L-Y, Mathews, V, and Koeffler, HP
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Human Genome ,Childhood Leukemia ,Pediatric Cancer ,Genetics ,Rare Diseases ,Hematology ,Clinical Research ,Pediatric ,Cell Differentiation ,DNA Mutational Analysis ,DNA-Binding Proteins ,Exome ,Gene Expression Profiling ,Humans ,Leukemia ,Promyelocytic ,Acute ,Nuclear Proteins ,Recurrence ,Transcription Factors ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
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- 2016
26. CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling
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Sun, Haibo, Lin, De-Chen, Cao, Qi, Guo, Xiao, Marijon, Helene, Zhao, Zhiqiang, Gery, Sigal, Xu, Liang, Yang, Henry, Pang, Brendan, Lee, Victor Kwan Min, Lim, Huey Jin, Doan, Ngan, Said, Jonathan W, Chu, Peiguo, Mayakonda, Anand, Thomas, Tom, Forscher, Charles, Baloglu, Erkan, Shacham, Sharon, Rajalingam, Raja, and Koeffler, H Phillip
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Pediatric ,Pediatric Cancer ,Rare Diseases ,Cancer ,Biotechnology ,Genetics ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Bone Neoplasms ,Cell Line ,Tumor ,Cell Survival ,Drug Synergism ,Female ,Gene Knockdown Techniques ,Humans ,Hydrazines ,Imidazoles ,Immunoblotting ,Immunohistochemistry ,Insulin-Like Growth Factor I ,Karyopherins ,Mice ,Mice ,Nude ,Oncogene Proteins ,Fusion ,Proto-Oncogene Protein c-fli-1 ,Pyrazines ,RNA-Binding Protein EWS ,Real-Time Polymerase Chain Reaction ,Receptors ,Cytoplasmic and Nuclear ,Sarcoma ,Ewing ,Signal Transduction ,Triazoles ,Xenograft Model Antitumor Assays ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9); 2687-97. ©2016 AACR.
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- 2016
27. Genomic landscape of liposarcoma
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Kanojia, Deepika, Nagata, Yasunobu, Garg, Manoj, Lee, Dhong Hyun, Sato, Aiko, Yoshida, Kenichi, Sato, Yusuke, Sanada, Masashi, Mayakonda, Anand, Bartenhagen, Christoph, Klein, Hans-Ulrich, Doan, Ngan B, Said, Jonathan W, Mohith, S, Gunasekar, Swetha, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Miyano, Satoru, Myklebost, Ola, Yang, Henry, Dugas, Martin, Meza-Zepeda, Leonardo A, Silberman, Allan W, Forscher, Charles, Tyner, Jeffrey W, Ogawa, Seishi, and Koeffler, H Phillip
- Subjects
Human Genome ,Cancer ,Rare Diseases ,Biotechnology ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,DNA Mutational Analysis ,Flow Cytometry ,Gene Knockdown Techniques ,Heterografts ,High-Throughput Nucleotide Sequencing ,Humans ,Liposarcoma ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Oligonucleotide Array Sequence Analysis ,Polymerase Chain Reaction ,Polymorphism ,Single Nucleotide ,Soft Tissue Neoplasms ,Transcriptome ,liposarcoma ,exome sequencing ,SNP array ,intra-tumor heterogeneity ,therapeutics ,Oncology and Carcinogenesis - Abstract
Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.
- Published
- 2015
28. Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone
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Pavlo Lutsik, Annika Baude, Daniela Mancarella, Simin Öz, Alexander Kühn, Reka Toth, Joschka Hey, Umut H. Toprak, Jinyeong Lim, Viet Ha Nguyen, Chao Jiang, Anand Mayakonda, Mark Hartmann, Felix Rosemann, Kersten Breuer, Dominik Vonficht, Florian Grünschläger, Suman Lee, Maren Kirstin Schuhmacher, Denis Kusevic, Anna Jauch, Dieter Weichenhan, Jozef Zustin, Matthias Schlesner, Simon Haas, Joo Hyun Park, Yoon Jung Park, Udo Oppermann, Albert Jeltsch, Florian Haller, Jörg Fellenberg, Anders M. Lindroth, and Christoph Plass
- Subjects
Science - Abstract
The histone variant mutation H3.3-G34W occurs in the majority of giant cell tumor of bone (GCTB). By profiling patient-derived GCTB tumor cells, the authors show that this mutation associates with epigenetic alterations in heterochromatic and bivalent regions that contribute to an impaired osteogenic differentiation and the osteolytic phenotype of GCTB.
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- 2020
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29. Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly
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Segrest, Jere P, Jones, Martin K, Catte, Andrea, Manchekar, Medha, Datta, Geeta, Zhang, Lei, Zhang, Robin, Li, Ling, Patterson, James C, Palgunachari, Mayakonda N, Oram, Jack F, and Ren, Gang
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Atherosclerosis ,Cardiovascular ,ATP Binding Cassette Transporter 1 ,Cell Membrane Structures ,Cholesterol ,Lipid Bilayers ,Lipoproteins ,HDL ,Molecular Dynamics Simulation ,Phosphatidylcholines ,Biophysics - Abstract
Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol.
- Published
- 2015
30. Genetic and Methylation Analysis of CTNNB1 in Benign and Malignant Melanocytic Lesions
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Anne Zaremba, Philipp Jansen, Rajmohan Murali, Anand Mayakonda, Anna Riedel, Dieter Krahl, Hans Burkhardt, Stefan John, Cyrill Géraud, Manuel Philip, Julia Kretz, Inga Möller, Nadine Stadtler, Antje Sucker, Annette Paschen, Selma Ugurel, Lisa Zimmer, Elisabeth Livingstone, Susanne Horn, Christoph Plass, Dirk Schadendorf, Eva Hadaschik, Pavlo Lutsik, and Klaus Griewank
- Subjects
deep penetrating nevus ,deep penetrating melanoma ,malignant melanoma ,mutation profiling ,immune checkpoint inhibition ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent CTNNB1 exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1–2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi and melanomas with CTNNB1 mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and melanoma. Malignant CTNNB1-mutant tumors (melanomas) demonstrated a different genetic profile, instead grouping clearly with other non-CTNNB1 melanomas in methylation assays. To further evaluate the role of CTNNB1 mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with CTNNB1 exon 3 mutations, including recurrent S45 (n = 13, 34%), G34 (n = 5, 13%), and S27 (n = 5, 13%) mutations. Locations and histological subtype of CTNNB1-mutated melanoma varied; none were reported as showing deep penetrating nevus-like morphology. The most frequent concurrent activating mutations were BRAF V600 (n = 21, 55%) and NRAS Q61 (n = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed disease control (partial response or stable disease). In summary, CTNNB1 mutations are associated with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic setting. In advanced disease, no clear characteristics distinguishing CTNNB1-mutant from other melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted.
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- 2022
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31. Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
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Ye Chen, Liang Xu, Anand Mayakonda, Mo-Li Huang, Deepika Kanojia, Tuan Zea Tan, Pushkar Dakle, Ruby Yu-Tong Lin, Xin-Yu Ke, Jonathan W. Said, Jianxiang Chen, Sigal Gery, Ling-Wen Ding, Yan-Yi Jiang, Angela Pang, Mark Edward Puhaindran, Boon Cher Goh, and H. Phillip Koeffler
- Subjects
Science - Abstract
Liposarcoma (LPS) is a rare cancer that can acquire resistance to chemotherapy. Here, the authors map super-enhancers in LPS, finding BET-protein dependent mechanisms that can be targeted by a BET protein degrader, which also can overcome acquired resistance to chemotherapy in LPS.
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- 2019
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32. Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques[S]
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G.M. Anantharamaiah, David W. Garber, Dennis Goldberg, Eric Morrel, Geeta Datta, Mayakonda N. Palgunachari, Thomas C. Register, Susan E. Appt, and C. Roger White
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peptides ,low density lipoprotein ,dyslipidemia ,lipoproteins ,apolipoprotein E ,Biochemistry ,QD415-436 - Abstract
Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141–150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential more, we designed and synthesized new analogues by linking ɑ-aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals. The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.
- Published
- 2018
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33. The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells
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Deepti Talwar, Colin G. Miller, Justus Grossmann, Lukasz Szyrwiel, Torsten Schwecke, Vadim Demichev, Ana-Matea Mikecin Drazic, Anand Mayakonda, Pavlo Lutsik, Carmen Veith, Michael D. Milsom, Karin Müller-Decker, Michael Mülleder, Markus Ralser, and Tobias P. Dick
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Physiology (medical) ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Cell Biology - Abstract
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity. Specifically, we find that anchorage-independent growth of cells and spheroids is limited by an elevation of endogenous peroxide levels and is largely dependent on a functional GAPDH redox switch. Likewise, tumour growth in vivo is limited by peroxide stress and suppressed when the GAPDH redox switch is disabled in tumour cells. The induction of additional intratumoural oxidative stress by chemo- or radiotherapy synergized with the deactivation of the GAPDH redox switch. Mice lacking the GAPDH redox switch exhibit altered fatty acid metabolism in kidney and heart, apparently in compensation for the lack of the redox switch. Together, our findings demonstrate the physiological and pathophysiological relevance of oxidative GAPDH inactivation in mammals.
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- 2023
34. Super-Enhancer-Driven Long Non-Coding RNA LINC01503, Regulated by TP63, Is Over-Expressed and Oncogenic in Squamous Cell Carcinoma
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Xie, Jian-Jun, Jiang, Yan-Yi, Jiang, Yuan, Li, Chun-Quan, Lim, Mei-Chee, An, Omer, Mayakonda, Anand, Ding, Ling-Wen, Long, Lin, Sun, Chun, Lin, Le-Hang, Chen, Li, Wu, Jian-Yi, Wu, Zhi-Yong, Cao, Qi, Fang, Wang-Kai, Yang, Wei, Soukiasian, Harmik, Meltzer, Stephen J., Yang, Henry, Fullwood, Melissa, Xu, Li-Yan, Li, En-Min, Lin, De-Chen, and Koeffler, H. Phillip
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- 2018
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35. Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
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Meriwether, David, Sulaiman, Dawoud, Volpe, Carmen, Dorfman, Anna, Grijalva, Victor, Dorreh, Nasrin, Solorzano-Vargas, R. Sergio, Wang, Jifang, O'Connor, Ellen, Papesh, Jeremy, Larauche, Muriel, Trost, Hannah, Palgunachari, Mayakonda N., Anantharamaiah, G.M., Herschman, Harvey R., Martin, Martin G., Fogelman, Alan M., and Reddy, Srinivasa T.
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COX-2 inhibitors -- Analysis ,Macrophages -- Analysis ,Lipids -- Analysis ,Inflammation -- Analysis ,Apolipoproteins -- Analysis ,Adalimumab -- Analysis ,Phospholipids ,Peptides ,Epithelium ,Piroxicam ,Health care industry - Abstract
Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high-fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2-KO but not WT mice. Cox2MKO increased proinflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2-MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, whereas administration of an LXA4 analog rescued disease in Cox2-MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2-MKO/CCHF and piroxicam-accelerated [Il10.sup.-/-] models of inflammatory bowel disease (IBD) and reduced elevated levels of proinflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2-MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides (a) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine-dependent (oxPAPC-dependent) proinflammatory responses in human macrophages and intestinal epithelium, and (b) directly cleared proinflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for proinflammatory and inflammation-resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD., Introduction Inflammatory bowel disease (IBD), inclusive of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. IBD consists of a dysregulated [...]
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- 2019
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36. ARID1A and CEBPα cooperatively inhibit UCA1 transcription in breast cancer
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Guo, Xiao, Zhang, Yin, Mayakonda, Anand, Madan, Vikas, Ding, Ling-Wen, Lin, Le-Hang, Zia, Saadiya, Gery, Sigal, Tyner, Jeffrey W., Zhou, Wu, Yin, Dong, Lin, De-Chen, and Koeffler, H. Phillip
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- 2018
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37. Profiling the B/T cell receptor repertoire of lymphocyte derived cell lines
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Kar-Tong Tan, Ling-Wen Ding, Qiao-Yang Sun, Zhen-Tang Lao, Wenwen Chien, Xi Ren, Jin-Fen Xiao, Xin Yi Loh, Liang Xu, Michael Lill, Anand Mayakonda, De-Chen Lin, Henry Yang, and H. Phillip Koeffler
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BCR/TCR receptor repertoire ,EBV lymphocytes ,Cancer cell lines ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Clonal VDJ rearrangement of B/T cell receptors (B/TCRs) occurring during B/T lymphocyte development has been used as a marker to track the clonality of B/T cell populations. Methods We systematically profiled the B/T cell receptor repertoire of 936 cancer cell lines across a variety of cancer types as well as 462 Epstein-Barr Virus (EBV) transformed normal B lymphocyte lines using RNA sequencing data. Results Rearranged B/TCRs were readily detected in cell lines derived from lymphocytes, and subclonality or potential biclonality were found in a number of blood cancer cell lines. Clonal BCR/TCR rearrangements were detected in several blast phase CML lines and unexpectedly, one gastric cancer cell line (KE-97), reflecting a lymphoid origin of these cells. Notably, clonality was highly prevalent in EBV transformed B lymphocytes, suggesting either transformation only occurred in a few B cells or those with a growth advantage dominated the transformed population through clonal evolution. Conclusions Our analysis reveals the complexity and heterogeneity of the BCR/TCR rearrangement repertoire and provides a unique insight into the clonality of lymphocyte derived cell lines.
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- 2018
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38. Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression
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Yuan Jiang, Yan-Yi Jiang, Jian-Jun Xie, Anand Mayakonda, Masaharu Hazawa, Li Chen, Jin-Fen Xiao, Chun-Quan Li, Mo-Li Huang, Ling-Wen Ding, Qiao-Yang Sun, Liang Xu, Deepika Kanojia, Maya Jeitany, Jian-Wen Deng, Lian-Di Liao, Harmik J. Soukiasian, Benjamin P. Berman, Jia-Jie Hao, Li-Yan Xu, En-Min Li, Ming-Rong Wang, Xin-Gang Bi, De-Chen Lin, and H. Phillip Koeffler
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Science - Abstract
Master regulator transcription factors TP63 and SOX2 have been reported to overlap in genomic occupancy in squamous cell carcinomas (SCCs). Here, the authors demonstrate that TP63 and SOX2 promote co-operatively long non-coding RNA CCAT1 expression through activating its super-enhancer, and CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR super-enhancers and enhances both the MEK/ERK1/2 and PI3K/AKT signaling pathways in SCC.
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- 2018
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39. Methrix: an R/Bioconductor package for systematic aggregation and analysis of bisulfite sequencing data.
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Anand Mayakonda, Maximilian Schönung, Joschka Hey, Rajbir Nath Batra, Clarissa Feuerstein-Akgoz, Kristin Köhler, Daniel B. Lipka, Rocio Sotillo, Christoph Plass, Pavlo Lutsik, and Reka Toth
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- 2021
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40. Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone
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Lutsik, Pavlo, Baude, Annika, Mancarella, Daniela, Öz, Simin, Kühn, Alexander, Toth, Reka, Hey, Joschka, Toprak, Umut H., Lim, Jinyeong, Nguyen, Viet Ha, Jiang, Chao, Mayakonda, Anand, Hartmann, Mark, Rosemann, Felix, Breuer, Kersten, Vonficht, Dominik, Grünschläger, Florian, Lee, Suman, Schuhmacher, Maren Kirstin, Kusevic, Denis, Jauch, Anna, Weichenhan, Dieter, Zustin, Jozef, Schlesner, Matthias, Haas, Simon, Park, Joo Hyun, Park, Yoon Jung, Oppermann, Udo, Jeltsch, Albert, Haller, Florian, Fellenberg, Jörg, Lindroth, Anders M., and Plass, Christoph
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- 2020
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41. Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response
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Chun-Shan Liu, Reka Toth, Ali Bakr, Ashish Goyal, Md Saiful Islam, Kersten Breuer, Anand Mayakonda, Yu-Yu Lin, Peter Stepper, Tomasz P. Jurkowski, Marlon R. Veldwijk, Elena Sperk, Carsten Herskind, Pavlo Lutsik, Dieter Weichenhan, Christoph Plass, Peter Schmezer, and Odilia Popanda
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bromodomain inhibitors ,DNA methylation ,EZH2 inhibitors ,radiotherapy-induced fibrosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis.
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- 2021
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42. Mutational profiling of acute lymphoblastic leukemia with testicular relapse
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Ling-Wen Ding, Qiao-Yang Sun, Anand Mayakonda, Kar-Tong Tan, Wenwen Chien, De-Chen Lin, Yan-Yi Jiang, Liang Xu, Manoj Garg, Zhen-Tang Lao, Michael Lill, Henry Yang, Allen Eng Juh Yeoh, and H. Phillip Koeffler
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Acute lymphoblastic leukemia ,ALL ,Testicular relapse ,Extramedullary relapse ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Relapsed acute lymphoblastic leukemia (ALL) is the leading cause of deaths of childhood cancer. Although relapse usually happens in the bone marrow, extramedullary relapse occasionally occurs including either the central nervous system or testis (
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- 2017
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43. Genetic and methylation profiles distinguish benign, malignant and spitzoid melanocytic tumors
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Anne Zaremba, Philipp Jansen, Rajmohan Murali, Anand Mayakonda, Anna Riedel, Manuel Philip, Christian Rose, Jörg Schaller, Hansgeorg Müller, Heinz Kutzner, Inga Möller, Nadine Stadtler, Julia Kretz, Antje Sucker, Agnes Bankfalvi, Elisabeth Livingstone, Lisa Zimmer, Susanne Horn, Annette Paschen, Christoph Plass, Dirk Schadendorf, Eva Hadaschik, Pavlo Lutsik, and Klaus Griewank
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Diagnosis, Differential ,Paraganglioma ,Cancer Research ,Skin Neoplasms ,DNA Copy Number Variations ,Oncology ,Nevus, Epithelioid and Spindle Cell ,Medizin ,Humans ,Syndrome ,Melanoma ,Methylation - Abstract
in press Accurate classification of melanocytic tumors is important for prognostic evaluation, treatment and follow-up protocols of patients. The majority of melanocytic proliferations can be classified solely based on clinical and pathological criteria, however in select cases a definitive diagnostic assessment remains challenging and additional diagnostic biomarkers would be advantageous. We analyzed melanomas, nevi, Spitz nevi and atypical spitzoid tumors using parallel sequencing (exons of 611 genes and 507 gene translocation analysis) and methylation arrays (850k Illumina EPIC). By combining detailed genetic and epigenetic analysis with reference-based and reference-free DNA methylome deconvolution we compared Spitz nevi to nevi and melanoma and assessed the potential for these methods in classifying challenging spitzoid tumors. Results were correlated with clinical and histologic features. Spitz nevi were found to cluster independently of nevi and melanoma and demonstrated a different mutation profile. Multiple copy number alterations and TERT promoter mutations were identified only in melanomas. Genome-wide methylation in Spitz nevi was comparable to benign nevi while the Leukocytes UnMethylation for Purity (LUMP) algorithm in Spitz nevi was comparable to melanoma. Histologically difficult to classify Spitz tumor cases were assessed which, based on methylation arrays, clustered between Spitz nevi and melanoma and in terms of genetic profile or copy number variations demonstrated worrisome features suggesting a malignant neoplasm. Comprehensive sequencing and methylation analysis verify Spitz nevi as an independent melanocytic entity distinct from both nevi and melanoma. Combined genetic and methylation assays can offer additional insights in diagnosing difficult to classify Spitzoid tumors.
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- 2022
44. Supplemental Tables S1-4 from Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma
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Lin, De-Chen, primary, Mayakonda, Anand, primary, Dinh, Huy Q., primary, Huang, Pinbo, primary, Lin, Lehang, primary, Liu, Xiaoping, primary, Ding, Ling-wen, primary, Wang, Jie, primary, Berman, Benjamin P., primary, Song, Er-Wei, primary, Yin, Dong, primary, and Koeffler, H. Phillip, primary
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- 2023
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45. Supplemental Figures from Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma
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Sun, Haibo, primary, Lin, De-Chen, primary, Cao, Qi, primary, Pang, Brendan, primary, Gae, David D., primary, Lee, Victor Kwan Min, primary, Lim, Huey Jin, primary, Doan, Ngan, primary, Said, Jonathan W., primary, Gery, Sigal, primary, Chow, Marilynn, primary, Mayakonda, Anand, primary, Forscher, Charles, primary, Tyner, Jeffrey W., primary, and Koeffler, H. Phillip, primary
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- 2023
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46. Supplemental Table S6-9 from Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma
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Lin, De-Chen, primary, Mayakonda, Anand, primary, Dinh, Huy Q., primary, Huang, Pinbo, primary, Lin, Lehang, primary, Liu, Xiaoping, primary, Ding, Ling-wen, primary, Wang, Jie, primary, Berman, Benjamin P., primary, Song, Er-Wei, primary, Yin, Dong, primary, and Koeffler, H. Phillip, primary
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- 2023
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47. Supplementary Fig.1-11 from Genomic and Epigenomic Heterogeneity of Hepatocellular Carcinoma
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Lin, De-Chen, primary, Mayakonda, Anand, primary, Dinh, Huy Q., primary, Huang, Pinbo, primary, Lin, Lehang, primary, Liu, Xiaoping, primary, Ding, Ling-wen, primary, Wang, Jie, primary, Berman, Benjamin P., primary, Song, Er-Wei, primary, Yin, Dong, primary, and Koeffler, H. Phillip, primary
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- 2023
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48. Supplementary Table 7 from Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma
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Yuan, Jiang, primary, Jiang, Yan-Yi, primary, Mayakonda, Anand, primary, Huang, Moli, primary, Ding, Ling-Wen, primary, Lin, Han, primary, Yu, Fenggang, primary, Lu, Yanan, primary, Loh, Thomas Kwok Seng, primary, Chow, Marilynn, primary, Savage, Samantha, primary, Tyner, Jeffrey W., primary, Lin, De-Chen, primary, and Koeffler, H. Phillip, primary
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- 2023
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49. Data from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
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Ding, Ling-Wen, primary, Sun, Qiao-Yang, primary, Tan, Kar-Tong, primary, Chien, Wenwen, primary, Thippeswamy, Anand Mayakonda, primary, Eng Juh Yeoh, Allen, primary, Kawamata, Norihiko, primary, Nagata, Yasunobu, primary, Xiao, Jin-Fen, primary, Loh, Xin-Yi, primary, Lin, De-Chen, primary, Garg, Manoj, primary, Jiang, Yan-Yi, primary, Xu, Liang, primary, Lim, Su-Lin, primary, Liu, Li-Zhen, primary, Madan, Vikas, primary, Sanada, Masashi, primary, Fernández, Lucia Torres, primary, Preethi, Hema, primary, Lill, Michael, primary, Kantarjian, Hagop M., primary, Kornblau, Steven M., primary, Miyano, Satoru, primary, Liang, Der-Cherng, primary, Ogawa, Seishi, primary, Shih, Lee-Yung, primary, Yang, Henry, primary, and Koeffler, H. Phillip, primary
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- 2023
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50. Supplemental Tables S1-S9 from Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma
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Sun, Haibo, primary, Lin, De-Chen, primary, Cao, Qi, primary, Pang, Brendan, primary, Gae, David D., primary, Lee, Victor Kwan Min, primary, Lim, Huey Jin, primary, Doan, Ngan, primary, Said, Jonathan W., primary, Gery, Sigal, primary, Chow, Marilynn, primary, Mayakonda, Anand, primary, Forscher, Charles, primary, Tyner, Jeffrey W., primary, and Koeffler, H. Phillip, primary
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- 2023
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