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JOURNAL ARTICLE
Tomoya Muto, Maria Guillamot, Jennifer Yeung, Jing Fang, Joshua Bennett, Bettina Nadorp, Audrey Lasry, Luna Zea Redondo, Kwangmin Choi, Yixiao Gong, Callum S Walker, Kathleen Hueneman, Lyndsey C Bolanos, Laura Barreyro, Lynn H Lee, Kenneth D Greis, Nikita Vasyliev, Alireza Khodadadi-Jamayran, Evgeny Nudler, Amaia Lujambio, Scott W Lowe, Iannis Aifantis, Daniel T Starczynowski
Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6...
February 3, 2022: Cell Stem Cell
#22
JOURNAL ARTICLE
Palaniraja Thandapani, Andreas Kloetgen, Matthew T Witkowski, Christina Glytsou, Anna K Lee, Eric Wang, Jingjing Wang, Sarah E LeBoeuf, Kleopatra Avrampou, Thales Papagiannakopoulos, Aristotelis Tsirigos, Iannis Aifantis
Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2 , the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR-Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand...
January 2022: Nature
#23
JOURNAL ARTICLE
Karen L Bride, Hai Hu, Anastasia Tikhonova, Tori J Fuller, Tiffaney L Vincent, Rawan Shraim, Marilyn M Li, William L Carroll, Elizabeth A Raetz, Iannis Aifantis, David T Teachey
Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKi) with cytotoxic agents...
August 1, 2022: Haematologica
#24
JOURNAL ARTICLE
Randie H Kim, Sofia Nomikou, Nicolas Coudray, George Jour, Zarmeena Dawood, Runyu Hong, Eduardo Esteva, Theodore Sakellaropoulos, Douglas Donnelly, Una Moran, Aristides Hatzimemos, Jeffrey S Weber, Narges Razavian, Iannis Aifantis, David Fenyo, Matija Snuderl, Richard Shapiro, Russell S Berman, Iman Osman, Aristotelis Tsirigos
Image-based analysis as a method for mutation detection can be advantageous in settings when tumor tissue is limited or unavailable for direct testing. In this study, we utilize two distinct and complementary machine-learning methods of analyzing whole-slide images for predicting mutated BRAF. In the first method, whole-slide images of melanomas from 256 patients were used to train a deep convolutional neural network to develop a fully automated model that first selects for tumor-rich areas (area under the curve = 0...
June 2022: Journal of Investigative Dermatology
#25
JOURNAL ARTICLE
Ilseyar Akhmetzyanova, Tonya Aaron, Phillip Galbo, Anastasia Tikhonova, Igor Dolgalev, Masato Tanaka, Iannis Aifantis, Deyou Zheng, Xingxing Zang, David Fooksman
Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169+ radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones...
September 28, 2021: Blood Advances
#26
JOURNAL ARTICLE
Qiao Lu, Jia Liu, Shuai Zhao, Maria Florencia Gomez Castro, Maudry Laurent-Rolle, Jianbo Dong, Xiaojuan Ran, Payal Damani-Yokota, Hongzhen Tang, Triantafyllia Karakousi, Juhee Son, Maria E Kaczmarek, Ze Zhang, Stephen T Yeung, Broc T McCune, Rita E Chen, Fei Tang, Xianwen Ren, Xufeng Chen, Jack C C Hsu, Marianna Teplova, Betty Huang, Haijing Deng, Zhilin Long, Tenny Mudianto, Shumin Jin, Peng Lin, Jasper Du, Ruochen Zang, Tina Tianjiao Su, Alberto Herrera, Ming Zhou, Renhong Yan, Jia Cui, James Zhu, Qiang Zhou, Tao Wang, Jianzhu Ma, Sergei B Koralov, Zemin Zhang, Iannis Aifantis, Leopoldo N Segal, Michael S Diamond, Kamal M Khanna, Kenneth A Stapleford, Peter Cresswell, Yue Liu, Siyuan Ding, Qi Xie, Jun Wang
Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain...
June 8, 2021: Immunity
#27
JOURNAL ARTICLE
Eric Wang, Hua Zhou, Bettina Nadorp, Geraldine Cayanan, Xufeng Chen, Anna H Yeaton, Sofia Nomikou, Matthew T Witkowski, Sonali Narang, Andreas Kloetgen, Palaniraja Thandapani, Niklas Ravn-Boess, Aristotelis Tsirigos, Iannis Aifantis
Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation...
April 1, 2021: Cell Stem Cell
#28
JOURNAL ARTICLE
Huizhong Xiong, Maicol Mancini, Michael Gobert, Shiqian Shen, Glaucia C Furtado, Sergio A Lira, Christopher N Parkhurst, Veronique Garambois, Muriel Brengues, Carlos E Tadokoro, Thomas Trimarchi, Gonzalo Gómez-López, Amartya Singh, Hossein Khiabanian, Sonia Minuzzo, Stefano Indraccolo, Camille Lobry, Iannis Aifantis, Daniel Herranz, Juan J Lafaille, Antonio Maraver
The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer...
2021: Theranostics
#29
COMMENT
Anastasia N Tikhonova, Iannis Aifantis
No abstract text is available yet for this article.
January 2021: Nature
#30
JOURNAL ARTICLE
Chao Ma, Matthew T Witkowski, Jacob Harris, Igor Dolgalev, Sheetal Sreeram, Weiyi Qian, Jie Tong, Xin Chen, Iannis Aifantis, Weiqiang Chen
B cell acute lymphoblastic leukemia (B-ALL) blasts hijack the bone marrow (BM) microenvironment to form chemoprotective leukemic BM "niches," facilitating chemoresistance and, ultimately, disease relapse. However, the ability to dissect these evolving, heterogeneous interactions among distinct B-ALL subtypes and their varying BM niches is limited with current in vivo methods. Here, we demonstrated an in vitro organotypic "leukemia-on-a-chip" model to emulate the in vivo B-ALL BM pathology and comparatively studied the spatial and genetic heterogeneity of the BM niche in regulating B-ALL chemotherapy resistance...
October 2020: Science Advances
#31
JOURNAL ARTICLE
Jingmei Hsu, Hsuan-Ting Huang, Chung-Tsai Lee, Avik Choudhuri, Nicola K Wilson, Brian J Abraham, Victoria Moignard, Iwo Kucinski, Shuqian Yu, R Katherine Hyde, Joanna Tober, Xiongwei Cai, Yan Li, Yalin Guo, Song Yang, Michael Superdock, Eirini Trompouki, Fernando J Calero-Nieto, Alireza Ghamari, Jing Jiang, Peng Gao, Long Gao, Vy Nguyen, Anne L Robertson, Ellen M Durand, Katie L Kathrein, Iannis Aifantis, Scott A Gerber, Wei Tong, Kai Tan, Alan B Cantor, Yi Zhou, P Paul Liu, Richard A Young, Berthold Göttgens, Nancy A Speck, Leonard I Zon
Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization...
September 22, 2020: Proceedings of the National Academy of Sciences of the United States of America
#32
JOURNAL ARTICLE
Dimitrios Papaioannou, Andreas Petri, Oliver M Dovey, Sara Terreri, Eric Wang, Frances A Collins, Lauren A Woodward, Allison E Walker, Deedra Nicolet, Felice Pepe, Prasanthi Kumchala, Marius Bill, Christopher J Walker, Malith Karunasiri, Krzysztof Mrózek, Miranda L Gardner, Virginia Camilotto, Nina Zitzer, Jonathan L Cooper, Xiongwei Cai, Xiaoqing Rong-Mullins, Jessica Kohlschmidt, Kellie J Archer, Michael A Freitas, Yi Zheng, Robert J Lee, Iannis Aifantis, George Vassiliou, Guramrit Singh, Sakari Kauppinen, Clara D Bloomfield, Adrienne M Dorrance, Ramiro Garzon
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
July 29, 2020: Nature Communications
#33
REVIEW
Anastasia N Tikhonova, Audrey Lasry, Rebecca Austin, Iannis Aifantis
Single-cell sequencing approaches offer exploration of tissue architecture at unprecedented resolution. These tools are especially powerful when deconvoluting highly specialized microenvironments, such as stem cell (SC) niches. Here, we review single-cell studies that map the cellular and transcriptional makeup of stem and progenitor niches and discuss how these high-resolution analyses fundamentally advance our understanding of how niche factors shape SC biology and activity. In-depth characterization of the blueprint of SC-niche crosstalk, as well as understanding how it becomes dysregulated, will undoubtedly inform the development of more efficient therapies for malignancies and other pathologies...
July 2, 2020: Cell Stem Cell
#34
JOURNAL ARTICLE
Natacha Bohin, Theresa M Keeley, Alexis J Carulli, Emily M Walker, Elizabeth A Carlson, Jie Gao, Iannis Aifantis, Christian W Siebel, Michael W Rajala, Martin G Myers, Jennifer C Jones, Constance D Brindley, Peter J Dempsey, Linda C Samuelson
Intestinal crypts have great capacity for repair and regeneration after intestinal stem cell (ISC) injury. Here, we define the cellular remodeling process resulting from ISC niche interruption by transient Notch pathway inhibition in adult mice. Although ISCs were retained, lineage tracing demonstrated a marked reduction in ISC function after Notch disruption. Surprisingly, Notch ligand-expressing Paneth cells were rapidly lost by apoptotic cell death. The ISC-Paneth cell changes were followed by a regenerative response, characterized by expansion of cells expressing Notch ligands Dll1 and Dll4, enhanced Notch signaling, and a proliferative surge...
July 14, 2020: Stem Cell Reports
#35
JOURNAL ARTICLE
Matthew T Witkowski, Igor Dolgalev, Nikki A Evensen, Chao Ma, Tiffany Chambers, Kathryn G Roberts, Sheetal Sreeram, Yuling Dai, Anastasia N Tikhonova, Audrey Lasry, Chunxu Qu, Deqing Pei, Cheng Cheng, Gabriel A Robbins, Joanna Pierro, Shanmugapriya Selvaraj, Valeria Mezzano, Marla Daves, Philip J Lupo, Michael E Scheurer, Cynthia A Loomis, Charles G Mullighan, Weiqiang Chen, Karen R Rabin, Aristotelis Tsirigos, William L Carroll, Iannis Aifantis
A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival...
June 8, 2020: Cancer Cell
#36
JOURNAL ARTICLE
Yalu Zhou, Cuijuan Han, Eric Wang, Adam H Lorch, Valentina Serafin, Byoung-Kyu Cho, Blanca T Gutierrez Diaz, Julien Calvo, Celestia Fang, Alireza Khodadadi-Jamayran, Tommaso Tabaglio, Christian Marier, Anna Kuchmiy, Limin Sun, George Yacu, Szymon K Filip, Qi Jin, Yoh-Hei Takahashi, David R Amici, Emily J Rendleman, Radhika Rawat, Silvia Bresolin, Maddalena Paganin, Cheng Zhang, Hu Li, Irawati Kandela, Yuliya Politanska, Hiam Abdala-Valencia, Marc L Mendillo, Ping Zhu, Bruno Palhais, Pieter Van Vlierberghe, Tom Taghon, Iannis Aifantis, Young Ah Goo, Ernesto Guccione, Adriana Heguy, Aristotelis Tsirigos, Keng Boon Wee, Rama K Mishra, Francoise Pflumio, Benedetta Accordi, Giuseppe Basso, Panagiotis Ntziachristos
Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival...
September 2020: Cancer Discovery
#37
REVIEW
Eric Wang, Iannis Aifantis
RNA splicing is an essential process that governs many aspects of cellular proliferation, survival, and differentiation. Considering the importance of RNA splicing in gene regulation, alterations in this pathway have been implicated in many human cancers. Large-scale genomic studies have uncovered a spectrum of splicing machinery mutations that contribute to tumorigenesis. Moreover, cancer cells are capable of hijacking the expression of RNA-binding proteins (RBPs), leading to dysfunctional gene splicing and tumor-specific dependencies...
May 17, 2020: Trends in Cancer
#38
JOURNAL ARTICLE
Balázs Koscsó, Sravya Kurapati, Richard R Rodrigues, Jelena Nedjic, Kavitha Gowda, Changsik Shin, Chetna Soni, Azree Zaffran Ashraf, Indira Purushothaman, Maryknoll Palisoc, Sulei Xu, Haoyu Sun, Sathi Babu Chodisetti, Eugene Lin, Matthias Mack, Yuka Imamura Kawasawa, Pingnian He, Ziaur S M Rahman, Iannis Aifantis, Natalia Shulzhenko, Andrey Morgun, Milena Bogunovic
Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type...
April 10, 2020: Science Immunology
#39
JOURNAL ARTICLE
Andreas Kloetgen, Palaniraja Thandapani, Panagiotis Ntziachristos, Yohana Ghebrechristos, Sofia Nomikou, Charalampos Lazaris, Xufeng Chen, Hai Hu, Sofia Bakogianni, Jingjing Wang, Yi Fu, Francesco Boccalatte, Hua Zhong, Elisabeth Paietta, Thomas Trimarchi, Yixing Zhu, Pieter Van Vlierberghe, Giorgio G Inghirami, Timothee Lionnet, Iannis Aifantis, Aristotelis Tsirigos
Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer-promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP-seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL...
April 2020: Nature Genetics
#40
JOURNAL ARTICLE
Charalampos Lazaris, Iannis Aifantis, Aristotelis Tsirigos
Mounting evidence links genetic lesions with genome topology alterations and aberrant gene activation. However, the role of epigenetic plasticity remains elusive. Emerging studies implicate DNA methylation, transcriptional elongation, long noncoding RNAs (lncRNAs), and CCCTC-binding factor (CTCF)-RNA interactions, but systematic approaches are needed to fully decipher the role of epigenetic plasticity in genome integrity and function.
March 2020: Trends in Cancer
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