46 results on '"Dakle P"'
Search Results
2. BlendSQL: A Scalable Dialect for Unifying Hybrid Question Answering in Relational Algebra
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Glenn, Parker, Dakle, Parag Pravin, Wang, Liang, and Raghavan, Preethi
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Computer Science - Computation and Language - Abstract
Many existing end-to-end systems for hybrid question answering tasks can often be boiled down to a "prompt-and-pray" paradigm, where the user has limited control and insight into the intermediate reasoning steps used to achieve the final result. Additionally, due to the context size limitation of many transformer-based LLMs, it is often not reasonable to expect that the full structured and unstructured context will fit into a given prompt in a zero-shot setting, let alone a few-shot setting. We introduce BlendSQL, a superset of SQLite to act as a unified dialect for orchestrating reasoning across both unstructured and structured data. For hybrid question answering tasks involving multi-hop reasoning, we encode the full decomposed reasoning roadmap into a single interpretable BlendSQL query. Notably, we show that BlendSQL can scale to massive datasets and improve the performance of end-to-end systems while using 35% fewer tokens. Our code is available and installable as a package at https://github.com/parkervg/blendsql., Comment: For associated codebase, see https://github.com/parkervg/blendsql
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- 2024
3. Towards leveraging LLMs for Conditional QA
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Hussain, Syed-Amad, Dakle, Parag Pravin, Rallabandi, SaiKrishna, and Raghavan, Preethi
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Computer Science - Computation and Language - Abstract
This study delves into the capabilities and limitations of Large Language Models (LLMs) in the challenging domain of conditional question-answering. Utilizing the Conditional Question Answering (CQA) dataset and focusing on generative models like T5 and UL2, we assess the performance of LLMs across diverse question types. Our findings reveal that fine-tuned LLMs can surpass the state-of-the-art (SOTA) performance in some cases, even without fully encoding all input context, with an increase of 7-8 points in Exact Match (EM) and F1 scores for Yes/No questions. However, these models encounter challenges in extractive question answering, where they lag behind the SOTA by over 10 points, and in mitigating the risk of injecting false information. A study with oracle-retrievers emphasizes the critical role of effective evidence retrieval, underscoring the necessity for advanced solutions in this area. Furthermore, we highlight the significant influence of evaluation metrics on performance assessments and advocate for a more comprehensive evaluation framework. The complexity of the task, the observed performance discrepancies, and the need for effective evidence retrieval underline the ongoing challenges in this field and underscore the need for future work focusing on refining training tasks and exploring prompt-based techniques to enhance LLM performance in conditional question-answering tasks.
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- 2023
4. Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations
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Su Lin Lim, Alisa Damnernsawad, Pavithra Shyamsunder, Wee Joo Chng, Bing Chen Han, Liang Xu, Jian Pan, Dakle Pushkar Pravin, Serhan Alkan, Jeffrey W. Tyner, and H. Phillip Koeffler
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation down-regulates MYC transcription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against multiple myeloma (MM) cells both in vitro and in vivo. In a dose-dependent manner, ARV 825 inhibited proliferation of 13 human MM cell lines and three fresh patient samples, and was associated with cell cycle arrest and apoptosis. ARV 825 rapidly and efficiently degraded BRD 2 and BRD 4. Sensitivity of MM cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were down-regulated by ARV 825. A total of 170 small molecule inhibitors were screened for synergy with ARV 825. Combination of ARV 825 with inhibitor of either dual PI3K/mTOR, CRM1, VEGFR, PDGFRα/b, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activity. Importantly, ARV 825 significantly inhibited the growth of MM xenografts and improved mice survival. Taken together, our results, in conjunction with recently published findings, provide a rationale for investigating the efficacy of ARV 825 for MM, use of cereblon as a biomarker for therapy of MM patients, and the combination of ARV 825 with small molecule inhibitors to improve the outcome of MM patients.
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- 2019
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5. Self-training Strategies for Sentiment Analysis: An Empirical Study
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Liu, Haochen, Rallabandi, Sai Krishna, Wu, Yijing, Dakle, Parag Pravin, and Raghavan, Preethi
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Computer Science - Computation and Language - Abstract
Sentiment analysis is a crucial task in natural language processing that involves identifying and extracting subjective sentiment from text. Self-training has recently emerged as an economical and efficient technique for developing sentiment analysis models by leveraging a small amount of labeled data and a large amount of unlabeled data. However, given a set of training data, how to utilize them to conduct self-training makes a significant difference in the final performance of the model. We refer to this methodology as the self-training strategy. In this paper, we present an empirical study of various self-training strategies for sentiment analysis. First, we investigate the influence of the self-training strategy and hyper-parameters on the performance of traditional small language models (SLMs) in various few-shot settings. Second, we also explore the feasibility of leveraging large language models (LLMs) to help self-training. We propose and empirically compare several self-training strategies with the intervention of LLMs. Extensive experiments are conducted on three real-world sentiment analysis datasets., Comment: Accepted by EACL Findings 2024
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- 2023
6. Correcting Semantic Parses with Natural Language through Dynamic Schema Encoding
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Glenn, Parker, Dakle, Parag Pravin, and Raghavan, Preethi
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Computer Science - Computation and Language - Abstract
In addressing the task of converting natural language to SQL queries, there are several semantic and syntactic challenges. It becomes increasingly important to understand and remedy the points of failure as the performance of semantic parsing systems improve. We explore semantic parse correction with natural language feedback, proposing a new solution built on the success of autoregressive decoders in text-to-SQL tasks. By separating the semantic and syntactic difficulties of the task, we show that the accuracy of text-to-SQL parsers can be boosted by up to 26% with only one turn of correction with natural language. Additionally, we show that a T5-base model is capable of correcting the errors of a T5-large model in a zero-shot, cross-parser setting., Comment: ACL 2023 Workshop on NLP for Conversational AI
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- 2023
7. HeySQuAD: A Spoken Question Answering Dataset
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Wu, Yijing, Rallabandi, SaiKrishna, Srinivasamurthy, Ravisutha, Dakle, Parag Pravin, Gon, Alolika, and Raghavan, Preethi
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Computer Science - Computation and Language ,Computer Science - Artificial Intelligence - Abstract
Spoken question answering (SQA) systems are critical for digital assistants and other real-world use cases, but evaluating their performance is a challenge due to the importance of human-spoken questions. This study presents a new large-scale community-shared SQA dataset called HeySQuAD, which includes 76k human-spoken questions, 97k machine-generated questions, and their corresponding textual answers from the SQuAD QA dataset. Our goal is to measure the ability of machines to accurately understand noisy spoken questions and provide reliable answers. Through extensive testing, we demonstrate that training with transcribed human-spoken and original SQuAD questions leads to a significant improvement (12.51%) in answering human-spoken questions compared to training with only the original SQuAD textual questions. Moreover, evaluating with a higher-quality transcription can lead to a further improvement of 2.03%. This research has significant implications for the development of SQA systems and their ability to meet the needs of users in real-world scenarios.
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- 2023
8. Understanding BLOOM: An empirical study on diverse NLP tasks
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Dakle, Parag Pravin, Rallabandi, SaiKrishna, and Raghavan, Preethi
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Computer Science - Computation and Language - Abstract
We view the landscape of large language models (LLMs) through the lens of the recently released BLOOM model to understand the performance of BLOOM and other decoder-only LLMs compared to BERT-style encoder-only models. We achieve this by evaluating the smaller BLOOM model variants (\textit{350m/560m} and \textit{1b3/1b7}) on several NLP benchmark datasets and popular leaderboards. We make the following observations: (1) BLOOM performance does not scale with parameter size, unlike other LLMs like GPT and BERT. Experiments fine-tuning BLOOM models show that the 560m variant performs similarly to or better than the 1b7 variant, (2) Zero-shot cross-lingual and multi-lingual fine-tuning experiments show that BLOOM is at par or worse than monolingual GPT-2 models, and (3) Toxicity analysis of prompt-based text generation using the RealToxicityPrompts dataset shows that the text generated by BLOOM is at least 17\% less toxic than GPT-2 and GPT-3 models.
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- 2022
9. Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)
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Kusuma, Frances Karla, Prabhu, Aishvaryaa, Tieo, Galen, Ahmed, Syed Moiz, Dakle, Pushkar, Yong, Wai Khang, Pathak, Elina, Madan, Vikas, Jiang, Yan Yi, Tam, Wai Leong, Kappei, Dennis, Dröge, Peter, Koeffler, H Phillip, and Jeitany, Maya
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Rare Diseases ,Cancer ,Genetics ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Telomere ,Cell Survival ,Signal Transduction ,Gene Expression Regulation ,DNA Repair ,DNA Replication ,JNK Mitogen-Activated Protein Kinases ,Humans ,Animals ,Mice ,Cell Line ,Tumor - Abstract
Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.
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- 2023
10. CEREC: A Corpus for Entity Resolution in Email Conversations
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Dakle, Parag Pravin and Moldovan, Dan I.
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Computer Science - Computation and Language ,Computer Science - Artificial Intelligence - Abstract
We present the first large scale corpus for entity resolution in email conversations (CEREC). The corpus consists of 6001 email threads from the Enron Email Corpus containing 36,448 email messages and 60,383 entity coreference chains. The annotation is carried out as a two-step process with minimal manual effort. Experiments are carried out for evaluating different features and performance of four baselines on the created corpus. For the task of mention identification and coreference resolution, a best performance of 59.2 F1 is reported, highlighting the room for improvement. An in-depth qualitative and quantitative error analysis is presented to understand the limitations of the baselines considered.
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- 2021
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11. Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas
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Jeitany, Maya, Prabhu, Aishvaryaa, Dakle, Pushkar, Pathak, Elina, Madan, Vikas, Kanojia, Deepika, Mukundan, Vineeth, Jiang, Yan Yi, Landesman, Yosef, Tam, Wai Leong, Kappei, Dennis, and Koeffler, H Phillip
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Rare Diseases ,Biotechnology ,Cancer ,Hematology ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Aetiology ,Antineoplastic Combined Chemotherapy Protocols ,Bortezomib ,Cell Line ,Tumor ,Cell Nucleus ,Drug Resistance ,Neoplasm ,Drug Synergism ,Fatty Acid Desaturases ,Gene Expression Regulation ,Neoplastic ,Humans ,Hydrazines ,Karyopherins ,Liposarcoma ,Oligopeptides ,Piperazines ,Proteasome Endopeptidase Complex ,Proteasome Inhibitors ,Receptors ,Cytoplasmic and Nuclear ,Triazoles ,Proteasome inhibitors ,Combinational therapies ,Physiology ,Clinical Sciences ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics ,Oncology and carcinogenesis - Abstract
Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.
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- 2021
12. 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
13. 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
14. 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
15. 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
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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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16. Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells
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Yun Wang, Long Cui, Peter Georgiev, Latika Singh, Yanyan Zheng, Ying Yu, Jeff Grein, Chunsheng Zhang, Eric S. Muise, David L. Sloman, Heidi Ferguson, Hongshi Yu, Cristina St. Pierre, Pranal J Dakle, Vincenzo Pucci, James Baker, Andrey Loboda, Doug Linn, Christopher Brynczka, Doug Wilson, Brian B Haines, Brian Long, Richard Wnek, Svetlana Sadekova, Michael Rosenzweig, Andrew Haidle, Yongxin Han, and Sheila H. Ranganath
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immunotherapy ,ep4 antagonism ,pge2 ,myeloid cells ,lymphocytes ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2–mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
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- 2021
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17. Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine
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Tahseen Abbas, Gaura Chaturvedi, P. Prakrithi, Ankit Kumar Pathak, Rintu Kutum, Pushkar Dakle, Ankita Narang, Vijeta Manchanda, Rutuja Patil, Dhiraj Aggarwal, Bhushan Girase, Ankita Srivastava, Manav Kapoor, Ishaan Gupta, Rajesh Pandey, Sanjay Juvekar, Debasis Dash, Mitali Mukerji, and Bhavana Prasher
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ayurgenomics ,deep phenotypes ,exomes ,precision medicine ,extreme phenotypes ,risk stratification ,Medicine - Abstract
Precision medicine aims to move from traditional reactive medicine to a system where risk groups can be identified before the disease occurs. However, phenotypic heterogeneity amongst the diseased and healthy poses a major challenge for identification markers for risk stratification and early actionable interventions. In Ayurveda, individuals are phenotypically stratified into seven constitution types based on multisystem phenotypes termed “Prakriti”. It enables the prediction of health and disease trajectories and the selection of health interventions. We hypothesize that exome sequencing in healthy individuals of phenotypically homogeneous Prakriti types might enable the identification of functional variations associated with the constitution types. Exomes of 144 healthy Prakriti stratified individuals and controls from two genetically homogeneous cohorts (north and western India) revealed differential risk for diseases/traits like metabolic disorders, liver diseases, and body and hematological measurements amongst healthy individuals. These SNPs differ significantly from the Indo-European background control as well. Amongst these we highlight novel SNPs rs304447 (IFIT5) and rs941590 (SERPINA10) that could explain differential trajectories for immune response, bleeding or thrombosis. Our method demonstrates the requirement of a relatively smaller sample size for a well powered study. This study highlights the potential of integrating a unique phenotyping approach for the identification of predictive markers and the at-risk population amongst the healthy.
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- 2022
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18. THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors
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Pavithra Shyamsunder, Shree Pooja Sridharan, Vikas Madan, Pushkar Dakle, Cao Zeya, Deepika Kanojia, Wee-Joo Chng, S. Tiong Ong, and H. Phillip Koeffler
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DNA repair ,BRCAness ,THZ531 ,Olaparib ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12–THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.
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- 2022
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19. Genetic variations in olfactory receptor gene OR2AG2 in a large multigenerational family with asthma
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Chakraborty, Samarpana, Dakle, Pushkar, Sinha, Anirban, Vishweswaraiah, Sangeetha, Nagori, Aditya, Salimath, Shivalingaswamy, Prakash, Y. S., Lodha, R., Kabra, S. K., Ghosh, Balaram, Faruq, Mohammed, Mahesh, P. A., and Agrawal, Anurag
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- 2019
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20. Dissecting the role of SWI/SNF component ARID1B in steady-state hematopoiesis
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Madan, Vikas, Shyamsunder, Pavithra, Dakle, Pushkar, Woon, Teoh Weoi, Han, Lin, Cao, Zeya, Nordin, Hazimah Binte Mohd, Jizhong, Shi, Shuizhou, Yu, Hossain, Md Zakir, and Koeffler, H. Phillip
- Abstract
•ARID1B regulates chromatin accessibility and gene expression in hematopoietic cells, and its loss affects myeloid reconstitution in mice.•Concurrent loss of ARID1A and ARID1B in the murine hematopoietic compartment leads to rapid mortality because of bone marrow failure.
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- 2023
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21. Identification of somatic alterations in lipoma using whole exome sequencing
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Kanojia, Deepika, Dakle, Pushkar, Mayakonda, Anand, Parameswaran, Rajeev, Puhaindran, Mark E., Min, Victor Lee Kwan, Madan, Vikas, and Koeffler, Phillip
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- 2019
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22. Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells.
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Sudipta Tripathi, Lola Chabtini, Pranal J Dakle, Brian Smith, Hisaya Akiba, Hideo Yagita, and Indira Guleria
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Medicine ,Science - Abstract
NK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells. Specifically we observed surface receptor phenotype and cytokine production by uNK cells following TIM-3 blockade. Our results show that TIM-3 plays a role in regulating the uNK cells and contributes to the maintenance of tolerance at the feto-maternal interface.
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- 2015
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23. Tim-4 Promotes Tolerance at the Fetomaternal Interface.: Abstract# D2774
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Tripathi, S., McGrath, M., Chabtini, L., Yeung, M., Dakle, P., Smith, B., and Guleria, I.
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- 2014
24. Identification of a novel enhancer of CEBPE essential for granulocytic differentiation
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Shyamsunder, Pavithra, Shanmugasundaram, Mahalakshmi, Mayakonda, Anand, Dakle, Pushkar, Teoh, Weoi Woon, Han, Lin, Kanojia, Deepika, Lim, Mei Chee, Fullwood, Melissa, An, Omer, Yang, Henry, Shi, Jizhong, Hossain, Mohammad Zakir, Madan, Vikas, and Koeffler, H. Phillip
- Abstract
CCAAT/enhancer binding protein e (CEBPE) is an essential transcription factor for granulocytic differentiation. Mutations of CEBPE occur in individuals with neutrophil-specific granule deficiency (SGD), which is characterized by defects in neutrophil maturation. Cebpe-knockout mice also exhibit defects in terminal differentiation of granulocytes, a phenotype reminiscent of SGD. Analysis of DNase I hypersensitive sites sequencing data revealed an open chromatin region 6 kb downstream of the transcriptional start site of Cebpe in murine myeloid cells. We identified an interaction between this +6-kb region and the core promoter of Cebpe using circular chromosome conformation capture sequencing (4C-seq). To understand the role of this putative enhancer in transcriptional regulation of Cebpe, we targeted it using catalytically inactive Cas9 fused to Krüppel-associated box (KRAB) domain and observed a significant downregulation of transcript and protein levels of CEBPE in cells expressing guide RNA targeting the +6-kb region. To further investigate the role of this novel enhancer further in myelopoiesis, we generated mice with deletion of this region using CRISPR/Cas9 technology. Germline deletion of the +6-kb enhancer resulted in reduced levels of CEBPE and its target genes and caused a severe block in granulocytic differentiation. We also identified binding of CEBPA and CEBPE to the +6-kb enhancer, which suggests their role in regulating the expression of Cebpe. In summary, we have identified a novel enhancer crucial for regulating expression of Cebpe and required for normal granulocytic differentiation.
- Published
- 2019
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25. Active maintenance of CD8+T cell naivety through regulation of global genome architecture
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Russ, Brendan E., Barugahare, Adele, Dakle, Pushkar, Tsyganov, Kirril, Quon, Sara, Yu, Bingfei, Li, Jasmine, Lee, Jason K.C., Olshansky, Moshe, He, Zhaohren, Harrison, Paul F., See, Michael, Nussing, Simone, Morey, Alison E., Udupa, Vibha A., Bennett, Taylah J., Kallies, Axel, Murre, Cornelis, Collas, Phillipe, Powell, David, Goldrath, Ananda W., and Turner, Stephen J.
- Abstract
The differentiation of naive CD8+T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+T cells. We observe that the architecture of the naive CD8+T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.
- Published
- 2023
- Full Text
- View/download PDF
26. Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells
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Tripathi, Sudipta, Chabtini, Lola, Dakle, Pranal J., Smith, Brian, Akiba, Hisaya, Yagita, Hideo, and Guleria, Indira
- Abstract
NK cells are the most abundant lymphocyte population in the feto-maternal interface during gestation. The uterine NK cells (uNK) are transient, have a unique immunophenotype and produce a number of cytokines. These cytokines play an important role in establishment and maintenance of vascular remodeling and tolerance associated with successful pregnancy. The uNK cells also express TIM-3 during gestation and blockade of TIM-3 expression results in fetal loss in mice. In this study we determined the effect of TIM-3 blockade on uNK cells. Specifically we observed surface receptor phenotype and cytokine production by uNK cells following TIM-3 blockade. Our results show that TIM-3 plays a role in regulating the uNK cells and contributes to the maintenance of tolerance at the feto-maternal interface.
- Published
- 2015
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27. B7h (ICOS-L) Maintains Tolerance at the Fetomaternal Interface
- Author
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Riella, Leonardo V., Dada, Shirine, Chabtini, Lola, Smith, Brian, Huang, Lei, Dakle, Pranal, Mfarrej, Bechara, D'Addio, Francesca, Adams, La-Tonya, Kochupurakkal, Nora, Vergani, Andrea, Fiorina, Paolo, Mellor, Andrew L., Sharpe, Arlene H., Yagita, Hideo, and Guleria, Indira
- Abstract
In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8+T cells) was observed in the anti-B7h–treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8+T cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8+T cells (in particular, CD8+CD103+cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8+effector response and reducing local immunomodulation mediated by CD8+regulatory T cells.
- Published
- 2013
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28. TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines.
- Author
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Jiang, Yan-Yi, Jiang, Yuan, Li, Chun-Quan, Zhang, Ying, Dakle, Pushkar, Kaur, Harvinder, Deng, Jian-Wen, Lin, Ruby Yu-Tong, Han, Lin, Xie, Jian-Jun, Yan, Yiwu, Doan, Ngan, Zheng, Yueyuan, Mayakonda, Anand, Hazawa, Masaharu, Xu, Liang, Li, YanYu, Aswad, Luay, Jeitany, Maya, and Kanojia, Deepika
- Abstract
We investigated the transcriptome of esophageal squamous cell carcinoma (ESCC) cells, activity of gene regulatory (enhancer and promoter regions), and the effects of blocking epigenetic regulatory proteins. We performed chromatin immunoprecipitation sequencing with antibodies against H3K4me1, H3K4me3, and H3K27ac and an assay for transposase-accessible chromatin to map the enhancer regions and accessible chromatin in 8 ESCC cell lines. We used the CRC_Mapper algorithm to identify core regulatory circuitry transcription factors in ESCC cell lines, and determined genome occupancy profiles for 3 of these factors. In ESCC cell lines, expression of transcription factors was knocked down with small hairpin RNAs, promoter and enhancer regions were disrupted by CRISPR/Cas9 genome editing, or bromodomains and extraterminal (BET) family proteins and histone deacetylases (HDACs) were inhibited with ARV-771 and romidepsin, respectively. ESCC cell lines were then analyzed by whole-transcriptome sequencing, immunoprecipitation, immunoblots, immunohistochemistry, and viability assays. Interactions between distal enhancers and promoters were identified and verified with circular chromosome conformation capture sequencing. NOD-SCID mice were given injections of modified ESCC cells, some mice where given injections of HDAC or BET inhibitors, and growth of xenograft tumors was measured. We identified super-enhancer-regulated circuits and transcription factors TP63, SOX2, and KLF5 as core regulatory factors in ESCC cells. Super-enhancer regulation of ALDH3A1 mediated by core regulatory factors was required for ESCC viability. We observed direct interactions between the promoter region of TP63 and functional enhancers, mediated by the core regulatory circuitry transcription factors. Deletion of enhancer regions from ESCC cells decreased expression of the core regulatory circuitry transcription factors and reduced cell viability; these same results were observed with knockdown of each core regulatory circuitry transcription factor. Incubation of ESCC cells with BET and HDAC disrupted the core regulatory circuitry program and the epigenetic modifications observed in these cells; mice given injections of HDAC or BET inhibitors developed smaller xenograft tumors from the ESCC cell lines. Xenograft tumors grew more slowly in mice given the combination of ARV-771 and romidepsin than mice given either agent alone. In epigenetic and transcriptional analyses of ESCC cell lines, we found the transcription factors TP63, SOX2, and KLF5 to be part of a core regulatory network that determines chromatin accessibility, epigenetic modifications, and gene expression patterns in these cells. A combination of epigenetic inhibitors slowed growth of xenograft tumors derived from ESCC cells in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. Combination of EP4antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells
- Author
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Wang, Yun, Cui, Long, Georgiev, Peter, Singh, Latika, Zheng, Yanyan, Yu, Ying, Grein, Jeff, Zhang, Chunsheng, Muise, Eric S., Sloman, David L., Ferguson, Heidi, Yu, Hongshi, Pierre, Cristina St., Dakle, Pranal J, Pucci, Vincenzo, Baker, James, Loboda, Andrey, Linn, Doug, Brynczka, Christopher, Wilson, Doug, Haines, Brian B, Long, Brian, Wnek, Richard, Sadekova, Svetlana, Rosenzweig, Michael, Haidle, Andrew, Han, Yongxin, and Ranganath, Sheila H.
- Abstract
ABSTRACTProstaglandin E2(PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2–mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4receptor. EP4inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitroexperiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+T-cells by PGE2and impaired suppression of CD8+T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2.In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2high TME. Our studies demonstrate that the combination of EP4blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.
- Published
- 2021
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30. ZRSR1 Cooperates with ZRSR2 in Regulating Splicing of U12-Type Introns in Murine Hematopoietic Cells
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Cao, Zeya, Madan, Vikas, Teoh, Weoi Woon, Dakle, Pushkar, Han, Lin, Shyamsunder, Pavithra, Zhou, Siqin, Li, Jia, Nordin, Hazimah Binte Mohd, Jizhong, Shi, Shuizhou, Yu, Yang, Henry, Hossain, Md Zakir, Chng, Wee-Joo, and Koeffler, H. Phillip
- Abstract
Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.
- Published
- 2020
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31. PML-RAR Binds to the +7kb Enhancer of CEBPE and Inhibits Its Expression
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Shyamsunder, Pavithra, Sridharan, Shree Pooja, Dakle, Pushkar, Cao, Zeya, Madan, Vikas, Ong, Sin Tiong, and Koeffler, H. Phillip
- Abstract
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The disease is identified by distinctive morphology and is distinguished by a balanced reciprocal translocation between chromosomes 15 and 17. This aberration leads to the fusion between promyelocytic leukemia (PML) gene located on chromosome 15q21, and retinoic acid receptor α (RARA) gene from chromosome 17q21, leading to the resultant chimeric onco-fusion protein PML-RARA, which is detectable in more than 95% patients and disturbs proper promyelocytic differentiation. All-trans retinoic acid (ATRA) can induce granulocytic differentiation in APL and is used to treat APL patients. Genes containing PML-RARA-targeted promoters are transcriptionally suppressed in APL and most likely constitute a major mechanism of transcriptional repression occurring in APL. A growing body of evidence points to the role of distal regulatory elements, including enhancers, in the control of gene expression. In order to understand the unique sets of enhancers that might be under the control of PML-RAR and crucial for granulocytic differentiation of NB4 cells, we analysed the enhancer landscape of control and ATRA treated NB4 cells. H3K9Ac mapping identified a repertoire of enhancers that were gained in NB4 cells treated with ATRA. Closer investigation of these enhancer elements revealed enrichment of H3K9Ac signals around major drivers of myeloid differentiation. Of note, we identified a gain in enhancer signature for a region about 7kb downstream of the CEBPE gene. Our previous studies identified a novel enhancer for CEBPE in murine hematopoietic cells, which was 6 downstream of CEBPE core promoter. It appears that the +7kb region we identified in human APL cells may be analogous to the murine enhancer. We also observed that PML-RAR binds this +7kb region and ATRA treatment of NB4 cells displaced binding of PML-RAR from the + 7kb region, suggestive of a transcriptional repressive effect of PML-RAR at such enhancer elements. To test the transcription regulating potential of this +7kb region, we used catalytically inactive Cas9 fused to Krüppel associated box (KRAB) domain (dCas9-KRAB). We designed three guide RNAs covering this regulatory region. The sgRNAs effectively repressed expression of CEBPE accompanied by lowered granulocytic differentiation of these guide RNA targeted NB4 cells after ATRA treatment.
- Published
- 2020
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32. ARID1A Is Critical for Maintaining Normal Hematopoiesis in Mice
- Author
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Han, Lin, Madan, Vikas, Mayakonda, Anand, Dakle, Pushkar, Teoh, Weoi Woon, Shyamsunder, Pavithra, Nordin, Hazimah Binte Mohd, Cao, Zeya, Sundaresan, Janani, Lei, Ienglam, Wang, Zhong, and Koeffler, H. Phillip
- Abstract
No relevant conflicts of interest to declare.
- Published
- 2018
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33. Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)
- Author
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Frances Karla Kusuma, Aishvaryaa Prabhu, Galen Tieo, Syed Moiz Ahmed, Pushkar Dakle, Wai Khang Yong, Elina Pathak, Vikas Madan, Yan Yi Jiang, Wai Leong Tam, Dennis Kappei, Peter Dröge, H. Phillip Koeffler, and Maya Jeitany
- Subjects
Science - Abstract
The kinase inhibitor Ponatinib inhibits an ABL1-JUN signalling axis and alters telomere homeostasis, reduces telomere synthesis, and provokes telomere dysfunction in cancer cells which employ the alternative lengthening of telomeres mechanisms.
- Published
- 2023
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34. Active maintenance of CD8+ T cell naivety through regulation of global genome architecture
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Brendan E. Russ, Adele Barugahare, Pushkar Dakle, Kirril Tsyganov, Sara Quon, Bingfei Yu, Jasmine Li, Jason K.C. Lee, Moshe Olshansky, Zhaohren He, Paul F. Harrison, Michael See, Simone Nussing, Alison E. Morey, Vibha A. Udupa, Taylah J. Bennett, Axel Kallies, Cornelis Murre, Phillipe Collas, David Powell, Ananda W. Goldrath, and Stephen J. Turner
- Subjects
CP: Immunology ,CP: Molecular biology ,Biology (General) ,QH301-705.5 - Abstract
Summary: The differentiation of naive CD8+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.
- Published
- 2023
- Full Text
- View/download PDF
35. ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells
- Author
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Vikas Madan, Zeya Cao, Weoi Woon Teoh, Pushkar Dakle, Lin Han, Pavithra Shyamsunder, Maya Jeitany, Siqin Zhou, Jia Li, Hazimah Binte Mohd Nordin, Jizhong Shi, Shuizhou Yu, Henry Yang, Md Zakir Hossain, Wee Joo Chng, and H. Phillip Koeffler
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. In order to further investigate the role of this splice factor in RNA splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not in human cells contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to accurately model ZRSR2-mutant MDS in mice.
- Published
- 2021
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36. ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion
- Author
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Vikas Madan, Lin Han, Norimichi Hattori, Weoi Woon Teoh, Anand Mayakonda, Qiao-Yang Sun, Ling-Wen Ding, Hazimah Binte Mohd Nordin, Su Lin Lim, Pavithra Shyamsunder, Pushkar Dakle, Janani Sundaresan, Ngan B. Doan, Masashi Sanada, Aiko Sato-Otsubo, Manja Meggendorfer, Henry Yang, Jonathan W. Said, Seishi Ogawa, Torsten Haferlach, Der-Cherng Liang, Lee-Yung Shih, Tsuyoshi Nakamaki, Q. Tian Wang, and H. Phillip Koeffler
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - 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.
- Published
- 2018
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37. CARD10, a CEBPE target involved in granulocytic differentiation
- Author
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Pavithra Shyamsunder, Haresh Sankar, Anand Mayakonda, Lin Han, Hazimah Binte Mohd Nordin, Teoh Weoi Woon, Mahalakshmi Shanmugasundaram, Pushkar Dakle, Vikas Madan, and H. Phillip Koeffler
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Maturation of granulocytes is dependent on controlled gene expression by myeloid lineage restricted transcription factors. CEBPE is one of the essential transcription factors required for granulocytic differentiation. Identification of downstream targets of CEBPE is vital to understand better its role in terminal granulopoiesis. In this study, we have identified Card10 as a novel target of CEBPE. We show that CEBPE binds to regulatory elements upstream of the murine Card10 locus, and expression of CARD10 is significantly reduced in Cebpe knock-out mice. Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis, affecting expression of genes involved in myeloid cell development and function. Taken together, our data demonstrate for the first time that Card10 is expressed in granulocytes and is a direct target of CEBPE with functions extending to myeloid differentiation.
- Published
- 2018
- Full Text
- View/download PDF
38. Active maintenance of CD8 + T cell naivety through regulation of global genome architecture.
- Author
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Russ BE, Barugahare A, Dakle P, Tsyganov K, Quon S, Yu B, Li J, Lee JKC, Olshansky M, He Z, Harrison PF, See M, Nussing S, Morey AE, Udupa VA, Bennett TJ, Kallies A, Murre C, Collas P, Powell D, Goldrath AW, and Turner SJ
- Subjects
- Cell Differentiation, Transcription Factors genetics, Immunologic Memory genetics, CD8-Positive T-Lymphocytes, Chromatin
- Abstract
The differentiation of naive CD8
+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state., Competing Interests: Declaration of interests A.W.G. is a member of the scientific advisory board of ArsenalBio. No funding from ArsenalBio was provided for this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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- View/download PDF
39. Targeting RNA Exonuclease XRN1 Potentiates Efficacy of Cancer Immunotherapy.
- Author
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Ran XB, Ding LW, Sun QY, Yang H, Said JW, Zhentang L, Madan V, Dakle P, Xiao JF, Loh X, Li Y, Xu L, Xiang XQ, Wang LZ, Goh BC, Lin DC, Chng WJ, Tan SY, Jha S, and Koeffler HP
- Subjects
- Animals, Mice, Exonucleases metabolism, Exoribonucleases genetics, Exoribonucleases metabolism, Immunotherapy, RNA Stability, Signal Transduction, Neoplasms genetics, Neoplasms therapy, RNA
- Abstract
Despite the remarkable clinical responses achieved with immune checkpoint blockade therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. Aberrant RNA accumulation can mediate IFN signaling and stimulate an immune response, suggesting that targeting RNA decay machinery might sensitize tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1, as a potential therapeutic target to suppress RNA decay and stimulate antitumor immunity. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy efficacy, while silencing of XRN1 alone did not affect tumor growth in immunodeficient mice. Mechanistically, XRN1 depletion activated IFN signaling and the viral defense pathway; both pathways play determinant roles in regulating immune evasion. Aberrant RNA-sensing signaling proteins (RIG-I/MAVS) mediated the expression of IFN genes, as depletion of each of them blunted the elevation of antiviral/IFN signaling in XRN1-silenced cells. Analysis of pan-cancer CRISPR-screening data indicated that IFN signaling triggered by XRN1 silencing is a common phenomenon, suggesting that the effect of XRN1 silencing may be extended to multiple types of cancers. Overall, XRN1 depletion triggers aberrant RNA-mediated IFN signaling, highlighting the importance of the aberrant RNA-sensing pathway in regulating immune responses. These findings provide the molecular rationale for developing XRN1 inhibitors and exploring their potential clinical application in combination with cancer immunotherapy., Significance: Targeting XRN1 activates an intracellular innate immune response mediated by RNA-sensing signaling and potentiates cancer immunotherapy efficacy, suggesting inhibition of RNA decay machinery as a novel strategy for cancer treatment., (©2023 American Association for Cancer Research.)
- Published
- 2023
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- View/download PDF
40. Whole Exome Sequencing in Healthy Individuals of Extreme Constitution Types Reveals Differential Disease Risk: A Novel Approach towards Predictive Medicine.
- Author
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Abbas T, Chaturvedi G, Prakrithi P, Pathak AK, Kutum R, Dakle P, Narang A, Manchanda V, Patil R, Aggarwal D, Girase B, Srivastava A, Kapoor M, Gupta I, Pandey R, Juvekar S, Dash D, Mukerji M, and Prasher B
- Abstract
Precision medicine aims to move from traditional reactive medicine to a system where risk groups can be identified before the disease occurs. However, phenotypic heterogeneity amongst the diseased and healthy poses a major challenge for identification markers for risk stratification and early actionable interventions. In Ayurveda, individuals are phenotypically stratified into seven constitution types based on multisystem phenotypes termed " Prakriti ". It enables the prediction of health and disease trajectories and the selection of health interventions. We hypothesize that exome sequencing in healthy individuals of phenotypically homogeneous Prakriti types might enable the identification of functional variations associated with the constitution types. Exomes of 144 healthy Prakriti stratified individuals and controls from two genetically homogeneous cohorts (north and western India) revealed differential risk for diseases/traits like metabolic disorders, liver diseases, and body and hematological measurements amongst healthy individuals. These SNPs differ significantly from the Indo-European background control as well. Amongst these we highlight novel SNPs rs304447 ( IFIT5 ) and rs941590 ( SERPINA10 ) that could explain differential trajectories for immune response, bleeding or thrombosis. Our method demonstrates the requirement of a relatively smaller sample size for a well powered study. This study highlights the potential of integrating a unique phenotyping approach for the identification of predictive markers and the at-risk population amongst the healthy.
- Published
- 2022
- Full Text
- View/download PDF
41. ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells.
- Author
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Madan V, Cao Z, Teoh WW, Dakle P, Han L, Shyamsunder P, Jeitany M, Zhou S, Li J, Nordin HBM, Shi J, Yu S, Yang H, Hossain MZ, Chng WJ, and Koeffler HP
- Subjects
- Animals, Introns, Mice, Mutation, Spliceosomes genetics, Myelodysplastic Syndromes genetics, RNA Splicing, Ribonucleoproteins genetics, Ribonucleoproteins metabolism, Splicing Factor U2AF genetics, Splicing Factor U2AF metabolism
- Abstract
Recurrent loss-of-function mutations of spliceosome gene, ZRSR2, occur in myelodysplastic syndromes (MDS). Mutation/loss of ZRSR2 in human myeloid cells primarily causes impaired splicing of the U12-type introns. In order to further investigate the role of this splice factor in RNA splicing and hematopoietic development, we generated mice lacking ZRSR2. Unexpectedly, Zrsr2-deficient mice developed normal hematopoiesis with no abnormalities in myeloid differentiation evident in either young or ≥1-year old knockout mice. Repopulation ability of Zrsr2-deficient hematopoietic stem cells was also unaffected in both competitive and non-competitive reconstitution assays. Myeloid progenitors lacking ZRSR2 exhibited mis-splicing of U12-type introns, however, this phenotype was moderate compared to the ZRSR2-deficient human cells. Our investigations revealed that a closely related homolog, Zrsr1, expressed in the murine hematopoietic cells, but not in human cells contributes to splicing of U12-type introns. Depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of the U12-type introns, thus highlighting a collective role of ZRSR1 and ZRSR2 in murine U12-spliceosome. We also demonstrate that aberrant retention of U12-type introns of MAPK9 and MAPK14 leads to their reduced protein expression. Overall, our findings highlight that both ZRSR1 and ZRSR2 are functional components of the murine U12-spliceosome, and depletion of both proteins is required to accurately model ZRSR2-mutant MDS in mice.
- Published
- 2022
- Full Text
- View/download PDF
42. THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors.
- Author
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Shyamsunder P, Sridharan SP, Madan V, Dakle P, Zeya C, Kanojia D, Chng WJ, Ong ST, and Koeffler HP
- Subjects
- Animals, Apoptosis, BRCA1 Protein genetics, BRCA2 Protein genetics, Cell Proliferation, Drug Therapy, Combination, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Multiple Myeloma genetics, Multiple Myeloma pathology, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Anilides pharmacology, Biomarkers, Tumor genetics, DNA Repair, Gene Expression Regulation, Neoplastic drug effects, Multiple Myeloma drug therapy, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Pyrimidines pharmacology, Synthetic Lethal Mutations
- Abstract
Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12-THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.
- Published
- 2022
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43. Topography of transcriptionally active chromatin in glioblastoma.
- Author
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Xu L, Chen Y, Huang Y, Sandanaraj E, Yu JS, Lin RY, Dakle P, Ke XY, Chong YK, Koh L, Mayakonda A, Nacro K, Hill J, Huang ML, Gery S, Lim SW, Huang Z, Xu Y, Chen J, Bai L, Wang S, Wakimoto H, Yeo TT, Ang BT, Müschen M, Tang C, Tan TZ, and Koeffler HP
- Subjects
- Chromatin genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Brain Neoplasms genetics, Brain Neoplasms pathology, Glioblastoma genetics, Glioblastoma pathology
- Abstract
Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer-driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2021
- Full Text
- View/download PDF
44. RNA-Binding Protein ZFP36L1 Suppresses Hypoxia and Cell-Cycle Signaling.
- Author
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Loh XY, Sun QY, Ding LW, Mayakonda A, Venkatachalam N, Yeo MS, Silva TC, Xiao JF, Doan NB, Said JW, Ran XB, Zhou SQ, Dakle P, Shyamsunder P, Koh AP, Huang RY, Berman BP, Tan SY, Yang H, Lin DC, and Koeffler HP
- Subjects
- 3' Untranslated Regions genetics, Animals, Breast Neoplasms mortality, Breast Neoplasms pathology, Butyrate Response Factor 1 genetics, Carcinogenesis genetics, Cell Cycle genetics, Cell Hypoxia genetics, Cell Line, Tumor, Cyclin D1 genetics, E2F1 Transcription Factor genetics, Epigenesis, Genetic, Female, Gene Knockdown Techniques, Humans, Mice, Mutation, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Messenger metabolism, RNA, Small Interfering metabolism, Urinary Bladder Neoplasms pathology, Xenograft Model Antitumor Assays, Zinc Fingers genetics, Breast Neoplasms genetics, Butyrate Response Factor 1 metabolism, Gene Expression Regulation, Neoplastic, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Urinary Bladder Neoplasms genetics
- Abstract
ZFP36L1 is a tandem zinc-finger RNA-binding protein that recognizes conserved adenylate-uridylate-rich elements (ARE) located in 3'untranslated regions (UTR) to mediate mRNA decay. We hypothesized that ZFP36L1 is a negative regulator of a posttranscriptional hub involved in mRNA half-life regulation of cancer-related transcripts. Analysis of in silico data revealed that ZFP36L1 was significantly mutated, epigenetically silenced, and downregulated in a variety of cancers. Forced expression of ZFP36L1 in cancer cells markedly reduced cell proliferation in vitro and in vivo , whereas silencing of ZFP36L1 enhanced tumor cell growth. To identify direct downstream targets of ZFP36L1, systematic screening using RNA pull-down of wild-type and mutant ZFP36L1 as well as whole transcriptome sequencing of bladder cancer cells {plus minus} tet-on ZFP36L1 was performed. A network of 1,410 genes was identified as potential direct targets of ZFP36L1. These targets included a number of key oncogenic transcripts such as HIF1A, CCND1, and E2F1. ZFP36L1 specifically bound to the 3'UTRs of these targets for mRNA degradation, thus suppressing their expression. Dual luciferase reporter assays and RNA electrophoretic mobility shift assays showed that wild-type, but not zinc-finger mutant ZFP36L1, bound to HIF1A 3'UTR and mediated HIF1A mRNA degradation, leading to reduced expression of HIF1A and its downstream targets. Collectively, our findings reveal an indispensable role of ZFP36L1 as a posttranscriptional safeguard against aberrant hypoxic signaling and abnormal cell-cycle progression. SIGNIFICANCE: RNA-binding protein ZFP36L1 functions as a tumor suppressor by regulating the mRNA stability of a number of mRNAs involved in hypoxia and cell-cycle signaling., (©2019 American Association for Cancer Research.)
- Published
- 2020
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- View/download PDF
45. CARD10 , a CEBPE target involved in granulocytic differentiation.
- Author
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Shyamsunder P, Sankar H, Mayakonda A, Han L, Nordin HBM, Woon TW, Shanmugasundaram M, Dakle P, Madan V, and Koeffler HP
- Subjects
- Animals, Binding Sites, Cell Line, Cells, Cultured, Gene Expression Regulation, Granulocytes metabolism, Humans, Mice, Myeloid Cells, Protein Binding, Transcription Factors genetics, CARD Signaling Adaptor Proteins metabolism, CCAAT-Enhancer-Binding Proteins physiology, Cell Differentiation, Granulocytes cytology
- Abstract
Maturation of granulocytes is dependent on controlled gene expression by myeloid lineage restricted transcription factors. CEBPE is one of the essential transcription factors required for granulocytic differentiation. Identification of downstream targets of CEBPE is vital to understand better its role in terminal granulopoiesis. In this study, we have identified Card10 as a novel target of CEBPE. We show that CEBPE binds to regulatory elements upstream of the murine Card10 locus, and expression of CARD10 is significantly reduced in Cebpe knock-out mice. Silencing Card10 in a human cell line and in murine primary cells impaired granulopoiesis, affecting expression of genes involved in myeloid cell development and function. Taken together, our data demonstrate for the first time that Card10 is expressed in granulocytes and is a direct target of CEBPE with functions extending to myeloid differentiation., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
- Full Text
- View/download PDF
46. Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation.
- Author
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Netravathi M, Kumari R, Kapoor S, Dakle P, Dwivedi MK, Roy SD, Pandey P, Saini J, Ramakrishna A, Navalli D, Satishchandra P, Pal PK, Kumar A, and Faruq M
- Subjects
- Animals, Ataxia complications, Ataxia pathology, Base Sequence, Brain Neoplasms complications, Brain Neoplasms pathology, Calcinosis complications, Calcinosis pathology, Central Nervous System Cysts complications, Central Nervous System Cysts pathology, Child, Genomics, Homozygote, Humans, India, Leukoencephalopathies complications, Leukoencephalopathies pathology, Male, Muscle Spasticity complications, Muscle Spasticity pathology, Pedigree, Phenotype, Receptors, Notch metabolism, Retinal Diseases complications, Retinal Diseases pathology, Seizures complications, Seizures pathology, Signal Transduction, Telomere genetics, Ataxia genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Brain Neoplasms genetics, Calcinosis genetics, Central Nervous System Cysts genetics, Dextrocardia complications, Exome genetics, Leukoencephalopathies genetics, Muscle Spasticity genetics, Mutation, Missense, Retinal Diseases genetics, Seizures genetics, Sequence Analysis, DNA, Telomere-Binding Proteins genetics
- Abstract
Background: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene., Case Presentation: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway., Conclusions: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.
- Published
- 2015
- Full Text
- View/download PDF
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