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151. Dynamic 3D chromosomal landscapes in acute leukemia

Author

Kloetgen, Andreas, primary, Thandapani, Palaniraja, additional, Ntziachristos, Panagiotis, additional, Ghebrechristos, Yohana, additional, Nomikou, Sofia, additional, Lazaris, Charalampos, additional, Chen, Xufeng, additional, Hu, Hai, additional, Bakogianni, Sofia, additional, Wang, Jingjing, additional, Fu, Yi, additional, Boccalatte, Francesco, additional, Zhong, Hua, additional, Paietta, Elisabeth, additional, Trimarchi, Thomas, additional, Zhu, Yixing, additional, van Vlierberghe, Pieter, additional, Inghirami, Giorgio G, additional, Lionnet, Timothee, additional, Aifantis, Iannis, additional, and Tsirigos, Aristotelis, additional

Published
2019
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152. 2029 - THE RELAPSED B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA IMMUNE MICROENVIRONMENT

Author

Witkowski, Matthew, primary, Dolgalev, Igor, additional, Evensen, Nikki, additional, Roberts, Kathryn, additional, Sreeram, Sheetal, additional, Dai, Yuling, additional, Tikhonova, Anastasia, additional, Loomis, Cynthia, additional, Mullighan, Charles, additional, Tsirigos, Aristotelis, additional, Carroll, William, additional, and Aifantis, Iannis, additional

Published
2019
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153. Author Correction: The bone marrow microenvironment at single-cell resolution

Author

Tikhonova, Anastasia N., primary, Dolgalev, Igor, additional, Hu, Hai, additional, Sivaraj, Kishor K., additional, Hoxha, Edlira, additional, Cuesta-Domínguez, Álvaro, additional, Pinho, Sandra, additional, Akhmetzyanova, Ilseyar, additional, Gao, Jie, additional, Witkowski, Matthew, additional, Guillamot, Maria, additional, Gutkin, Michael C., additional, Zhang, Yutong, additional, Marier, Christian, additional, Diefenbach, Catherine, additional, Kousteni, Stavroula, additional, Heguy, Adriana, additional, Zhong, Hua, additional, Fooksman, David R., additional, Butler, Jason M., additional, Economides, Aris, additional, Frenette, Paul S., additional, Adams, Ralf H., additional, Satija, Rahul, additional, Tsirigos, Aristotelis, additional, and Aifantis, Iannis, additional

Published
2019
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154. Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment

Author

Chen, Xufeng, primary, Glytsou, Christina, additional, Zhou, Hua, additional, Narang, Sonali, additional, Reyna, Denis E., additional, Lopez, Andrea, additional, Sakellaropoulos, Theodore, additional, Gong, Yixiao, additional, Kloetgen, Andreas, additional, Yap, Yoon Sing, additional, Wang, Eric, additional, Gavathiotis, Evripidis, additional, Tsirigos, Aristotelis, additional, Tibes, Raoul, additional, and Aifantis, Iannis, additional

Published
2019
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155. Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Author

Wang, Eric, primary, Lu, Sydney X., additional, Pastore, Alessandro, additional, Chen, Xufeng, additional, Imig, Jochen, additional, Chun-Wei Lee, Stanley, additional, Hockemeyer, Kathryn, additional, Ghebrechristos, Yohana E., additional, Yoshimi, Akihide, additional, Inoue, Daichi, additional, Ki, Michelle, additional, Cho, Hana, additional, Bitner, Lillian, additional, Kloetgen, Andreas, additional, Lin, Kuan-Ting, additional, Uehara, Taisuke, additional, Owa, Takashi, additional, Tibes, Raoul, additional, Krainer, Adrian R., additional, Abdel-Wahab, Omar, additional, and Aifantis, Iannis, additional

Published
2019
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157. Assessing quality and completeness of human transcriptional regulatory pathways on a genome-wide scale

Author

Aifantis Iannis, Tang Zuojian, Shmelkov Evgeny, and Statnikov Alexander

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Background Pathway databases are becoming increasingly important and almost omnipresent in most types of biological and translational research. However, little is known about the quality and completeness of pathways stored in these databases. The present study conducts a comprehensive assessment of transcriptional regulatory pathways in humans for seven well-studied transcription factors: MYC, NOTCH1, BCL6, TP53, AR, STAT1, and RELA. The employed benchmarking methodology first involves integrating genome-wide binding with functional gene expression data to derive direct targets of transcription factors. Then the lists of experimentally obtained direct targets are compared with relevant lists of transcriptional targets from 10 commonly used pathway databases. Results The results of this study show that for the majority of pathway databases, the overlap between experimentally obtained target genes and targets reported in transcriptional regulatory pathway databases is surprisingly small and often is not statistically significant. The only exception is MetaCore pathway database which yields statistically significant intersection with experimental results in 84% cases. Additionally, we suggest that the lists of experimentally derived direct targets obtained in this study can be used to reveal new biological insight in transcriptional regulation and suggest novel putative therapeutic targets in cancer. Conclusions Our study opens a debate on validity of using many popular pathway databases to obtain transcriptional regulatory targets. We conclude that the choice of pathway databases should be informed by solid scientific evidence and rigorous empirical evaluation. Reviewers This article was reviewed by Prof. Wing Hung Wong, Dr. Thiago Motta Venancio (nominated by Dr. L Aravind), and Prof. Geoff J McLachlan.

Published
2011
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158. A RORγt+cell instructs gut microbiota-specific Tregcell differentiation

Author

Kedmi, Ranit, Najar, Tariq A., Mesa, Kailin R., Grayson, Allyssa, Kroehling, Lina, Hao, Yuhan, Hao, Stephanie, Pokrovskii, Maria, Xu, Mo, Talbot, Jhimmy, Wang, Jiaxi, Germino, Joe, Lareau, Caleb A., Satpathy, Ansuman T., Anderson, Mark S., Laufer, Terri M., Aifantis, Iannis, Bartleson, Juliet M., Allen, Paul M., Paidassi, Helena, Gardner, James M., Stoeckius, Marlon, and Littman, Dan R.

Abstract

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn’s disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacterspecies induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg(iTreg) cells are compromised3,4. How Helicobacterand other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTregcell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Tregcells. These RORγt+cells—probably type 3 innate lymphoid cells and/or Janus cells5—require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αvintegrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTregcells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

Published
2022
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159. TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis

Author

Dominguez, Pilar M., primary, Ghamlouch, Hussein, additional, Rosikiewicz, Wojciech, additional, Kumar, Parveen, additional, Béguelin, Wendy, additional, Fontán, Lorena, additional, Rivas, Martín A., additional, Pawlikowska, Patrycja, additional, Armand, Marine, additional, Mouly, Enguerran, additional, Torres-Martin, Miguel, additional, Doane, Ashley S., additional, Calvo Fernandez, María T., additional, Durant, Matt, additional, Della-Valle, Veronique, additional, Teater, Matt, additional, Cimmino, Luisa, additional, Droin, Nathalie, additional, Tadros, Saber, additional, Motanagh, Samaneh, additional, Shih, Alan H., additional, Rubin, Mark A., additional, Tam, Wayne, additional, Aifantis, Iannis, additional, Levine, Ross L., additional, Elemento, Olivier, additional, Inghirami, Giorgio, additional, Green, Michael R., additional, Figueroa, Maria E., additional, Bernard, Olivier A., additional, Aoufouchi, Said, additional, Li, Sheng, additional, Shaknovich, Rita, additional, and Melnick, Ari M., additional

Published
2018
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160. Oncogenic-Drivers Dictate Immune Responses to Control Disease Progression in Acute Myeloid Leukaemia

Author

Austin, Rebecca, primary, Bywater, Megan, additional, Straube, Jasmin, additional, Cooper, Leanne T, additional, Headlam, Madeleine, additional, Dave, Keyur, additional, Braun, Matthias, additional, Bald, Tobias, additional, Guimaraes, Fernando, additional, Jacquelin, Sebastien, additional, Witkowski, Matthew, additional, Aifantis, Iannis, additional, Hill, Geoffrey R, additional, Smyth, Mark J, additional, and Lane, Steven W., additional

Published
2018
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161. Therapeutic Targeting of an RNA Splicing Factor Network for the Treatment of Myeloid Neoplasms

Author

Lu, Sydney X., primary, Wang, Eric, additional, Pastore, Alessandro, additional, Xufeng, Chen, additional, Imig, Jochen, additional, Lee, Stanley C, additional, Ghebrechristos, Yohana, additional, Yoshimi, Akihide, additional, Bitner, Lillian E, additional, Ki, Michelle, additional, Kloetgen, Andreas, additional, Lin, Kuan-Ting, additional, Tibes, Raoul, additional, Krainer, Adrian R., additional, Uehara, Taisuke, additional, Owa, Takashi, additional, Aifantis, Iannis, additional, and Abdel-Wahab, Omar I, additional

Published
2018
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162. Donor T Cells Require Notch Signals but Not Alloantigen Presentation from Specialized Secondary Lymphoid Organ Fibroblasts to Drive Graft-Versus-Host Disease

Author

Perkey, Eric, primary, Carrington, Léolène, additional, Chung, Jooho, additional, Granadier, David, additional, Dils, Alexander, additional, Friedman, Ann, additional, Tikhonova, Anastasia, additional, Blazar, Bruce R., additional, Koch, Ute, additional, Labrecque, Nathalie, additional, Radtke, Freddy, additional, Siebel, Chris, additional, Aifantis, Iannis, additional, and Maillard, Ivan, additional

Published
2018
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166. Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.

Author

Huizhong Xiong, Mancini, Maicol, Gobert, Michael, Shiqian Shen, Furtado, Glaucia C., Lira, Sergio A., Parkhurst, Christopher N., Garambois, Veronique, Brengues, Muriel, Tadokoro, Carlos E., Trimarchi, Thomas, Gómez-López, Gonzalo, Singh, Amartya, Khiabanian, Hossein, Minuzzo, Sonia, Indraccolo, Stefano, Lobry, Camille, Aifantis, Iannis, Herranz, Daniel, and Lafaille, Juan J.

Published
2021
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167. Oncogenic-drivers dictate immune responses to control disease progression in acute myeloid leukaemia

Author

Austin, Rebecca, Bywater, Megan, Straube, Jasmine, Cooper, Leanne T., Headlam, Madeleine, Dave, Keyur, Matthias, Braun, Bald, Tobias, Guimaraes, Fernando, Jacquelin, Sebastien, Witkowski, Matthew, Aifantis, Iannis, Hill, Geoffrey R., Smythe, Mark J., Lane, Steven W., Austin, Rebecca, Bywater, Megan, Straube, Jasmine, Cooper, Leanne T., Headlam, Madeleine, Dave, Keyur, Matthias, Braun, Bald, Tobias, Guimaraes, Fernando, Jacquelin, Sebastien, Witkowski, Matthew, Aifantis, Iannis, Hill, Geoffrey R., Smythe, Mark J., and Lane, Steven W.

Abstract

Immunotherapy has revolutionised therapeutic approaches to fight cancer and, in certain diseases dramatically improves survival. Clinical responses to immune checkpoint blockade have in part been attributed to high mutational burden of tumours such as melanoma. High-risk acute myeloid leukaemia (AML) is defined by molecular and cytogenetic factors. AML has a low prevalence of somatic mutations and is predicted to have low immunogenicity. We aimed to determine how AMLs driven from different classes of oncogenes interact with endogenous anti-leukemic immune responses.

Published
2018

168. Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia

Author

Hubrecht Institute with UMC, Kourtis, Nikos, Lazaris, Charalampos, Hockemeyer, Kathryn, Balandrán, Juan Carlos, Jimenez, Alejandra R., Mullenders, Jasper, Gong, Yixiao, Trimarchi, Thomas, Bhatt, Kamala, Hu, Hai, Shrestha, Liza, Ambesi-Impiombato, Alberto, Kelliher, Michelle, Paietta, Elisabeth, Chiosis, Gabriela, Guzman, Monica L., Ferrando, Adolfo A., Tsirigos, Aristotelis, Aifantis, Iannis, Hubrecht Institute with UMC, Kourtis, Nikos, Lazaris, Charalampos, Hockemeyer, Kathryn, Balandrán, Juan Carlos, Jimenez, Alejandra R., Mullenders, Jasper, Gong, Yixiao, Trimarchi, Thomas, Bhatt, Kamala, Hu, Hai, Shrestha, Liza, Ambesi-Impiombato, Alberto, Kelliher, Michelle, Paietta, Elisabeth, Chiosis, Gabriela, Guzman, Monica L., Ferrando, Adolfo A., Tsirigos, Aristotelis, and Aifantis, Iannis

Published
2018

169. Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα

Author

Akhmetzyanova, Ilseyar, Aaron, Tonya, Galbo, Phillip, Tikhonova, Anastasia, Dolgalev, Igor, Tanaka, Masato, Aifantis, Iannis, Zheng, Deyou, Zang, Xingxing, and Fooksman, David

Abstract

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. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) by tumor-associated MPs. Exogenous intravenous IL-6 and TNFα can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNFα or TNFα receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169+ MPs.

Published
2021
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170. Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ.

Author

Koscsó, Balázs, Kurapati, Sravya, Rodrigues, Richard R., Nedjic, Jelena, Gowda, Kavitha, Shin, Changsik, Soni, Chetna, Ashraf, Azree Zaffran, Purushothaman, Indira, Palisoc, Maryknoll, Xu, Sulei, Sun, Haoyu, Chodisetti, Sathi Babu, Lin, Eugene, Mack, Matthias, Kawasawa, Yuka Imamura, He, Pingnian, Rahman, Ziaur S. M., Aifantis, Iannis, and Shulzhenko, Natalia

Abstract

Follicle Architects in the Colonic Mucosa Experimental Salmonella infections in the colon of mice are associated with a heterogeneous infiltrate of inflammatory myeloid cells including a predominance of cells expressing the CX3CR1 chemokine receptor. Koscsó et al. used a fluorescent reporter mouse strain to separate the inflammatory myeloid infiltrate into subsets of cells with low, intermediate, and high levels of CX3CR1 expression. RNA sequencing analysis provided clues to the functional roles of each subset. The CX3CR1hi macrophages were enriched within tertiary lymphoid structures that developed at mucosal sites of Salmonella invasion and contributed to induction of localized IgA antibody responses to Salmonella through expression of CXCL13, TGF-β1, and IL-10. These findings enhance our understanding of the functional diversification of the macrophage subsets associated with colonic inflammation. 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. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2+CX3CR1lo, Ccr7+CX3CR1int (lymph migratory), and Cxcl13+CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13+CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Published
2020
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173. Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia

Author

Kourtis, Nikos, primary, Lazaris, Charalampos, additional, Hockemeyer, Kathryn, additional, Balandrán, Juan Carlos, additional, Jimenez, Alejandra R., additional, Mullenders, Jasper, additional, Gong, Yixiao, additional, Trimarchi, Thomas, additional, Bhatt, Kamala, additional, Hu, Hai, additional, Shrestha, Liza, additional, Ambesi-Impiombato, Alberto, additional, Kelliher, Michelle, additional, Paietta, Elisabeth, additional, Chiosis, Gabriela, additional, Guzman, Monica L., additional, Ferrando, Adolfo A., additional, Tsirigos, Aristotelis, additional, and Aifantis, Iannis, additional

Published
2018
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175. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche

Author

Chakrabarti, Rumela, primary, Celià-Terrassa, Toni, additional, Kumar, Sushil, additional, Hang, Xiang, additional, Wei, Yong, additional, Choudhury, Abrar, additional, Hwang, Julie, additional, Peng, Jia, additional, Nixon, Briana, additional, Grady, John J., additional, DeCoste, Christina, additional, Gao, Jie, additional, van Es, Johan H., additional, Li, Ming O., additional, Aifantis, Iannis, additional, Clevers, Hans, additional, and Kang, Yibin, additional

Published
2018
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177. Role of Dysregulated Cytokine Signaling and Bacterial Triggers in the Pathogenesis of Cutaneous T-Cell Lymphoma

Author

Fanok, Melania H., primary, Sun, Amy, additional, Fogli, Laura K., additional, Narendran, Vijay, additional, Eckstein, Miriam, additional, Kannan, Kasthuri, additional, Dolgalev, Igor, additional, Lazaris, Charalampos, additional, Heguy, Adriana, additional, Laird, Mary E., additional, Sundrud, Mark S., additional, Liu, Cynthia, additional, Kutok, Jeff, additional, Lacruz, Rodrigo S., additional, Latkowski, Jo-Ann, additional, Aifantis, Iannis, additional, Ødum, Niels, additional, Hymes, Kenneth B., additional, Goel, Swati, additional, and Koralov, Sergei B., additional

Published
2018
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178. Rapid crypt cell remodeling regenerates the intestinal stem cell niche after stem cell loss induced by Notch inhibition

Author

Bohin, Natacha, primary, Keeley, Theresa M., additional, Carulli, Alexis J., additional, Carlson, Elizabeth A., additional, Gao, Jie, additional, Aifantis, Iannis, additional, Rajala, Michael W., additional, Myers, Martin G., additional, Jones, Jennifer C., additional, Brindley, Constance D., additional, Dempsey, Peter J., additional, and Samuelson, Linda C., additional

Published
2018
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180. AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis

Author

Teater, Matt, primary, Dominguez, Pilar M., additional, Redmond, David, additional, Chen, Zhengming, additional, Ennishi, Daisuke, additional, Scott, David W., additional, Cimmino, Luisa, additional, Ghione, Paola, additional, Chaudhuri, Jayanta, additional, Gascoyne, Randy D., additional, Aifantis, Iannis, additional, Inghirami, Giorgio, additional, Elemento, Olivier, additional, Melnick, Ari, additional, and Shaknovich, Rita, additional

Published
2018
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182. BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.

Author

Valls, Ester, Valls, Ester, Lobry, Camille, Geng, Huimin, Wang, Ling, Cardenas, Mariano, Rivas, Martín, Cerchietti, Leandro, Oh, Philmo, Yang, Shao Ning, Oswald, Erin, Graham, Camille W, Jiang, Yanwen, Hatzi, Katerina, Agirre, Xabier, Perkey, Eric, Li, Zhuoning, Tam, Wayne, Bhatt, Kamala, Leonard, John P, Zweidler-McKay, Patrick A, Maillard, Ivan, Elemento, Olivier, Ci, Weimin, Aifantis, Iannis, Melnick, Ari, Valls, Ester, Valls, Ester, Lobry, Camille, Geng, Huimin, Wang, Ling, Cardenas, Mariano, Rivas, Martín, Cerchietti, Leandro, Oh, Philmo, Yang, Shao Ning, Oswald, Erin, Graham, Camille W, Jiang, Yanwen, Hatzi, Katerina, Agirre, Xabier, Perkey, Eric, Li, Zhuoning, Tam, Wayne, Bhatt, Kamala, Leonard, John P, Zweidler-McKay, Patrick A, Maillard, Ivan, Elemento, Olivier, Ci, Weimin, Aifantis, Iannis, and Melnick, Ari

Abstract

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2Significance: We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506-21. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

Published
2017

183. TET1 is a tumor suppressor of hematopoietic malignancy

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Dawlaty, Meelad M, Jaenisch, Rudolf, Cimmino, Luisa, Ndiaye-Lobry, Delphine, Yap, Yoon Sing, Bakogianni, Sofia, Yu, Yiting, Bhattacharyya, Sanchari, Shaknovich, Rita, Geng, Huimin, Lobry, Camille, Mullenders, Jasper, King, Bryan, Trimarchi, Thomas, Aranda-Orgilles, Beatriz, Liu, Cynthia, Shen, Steven, Verma, Amit K, Aifantis, Iannis, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Dawlaty, Meelad M, Jaenisch, Rudolf, Cimmino, Luisa, Ndiaye-Lobry, Delphine, Yap, Yoon Sing, Bakogianni, Sofia, Yu, Yiting, Bhattacharyya, Sanchari, Shaknovich, Rita, Geng, Huimin, Lobry, Camille, Mullenders, Jasper, King, Bryan, Trimarchi, Thomas, Aranda-Orgilles, Beatriz, Liu, Cynthia, Shen, Steven, Verma, Amit K, and Aifantis, Iannis

Abstract

The methylcytosine dioxygenase TET1 (‘ten-eleven translocation 1’) is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy., National Institutes of Health (U.S.) (5RO1HD045022), National Institutes of Health (U.S.) (5R37CA084198)

Published
2017

185. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

Author

Cimmino, Luisa, primary, Dolgalev, Igor, additional, Wang, Yubao, additional, Yoshimi, Akihide, additional, Martin, Gaëlle H., additional, Wang, Jingjing, additional, Ng, Victor, additional, Xia, Bo, additional, Witkowski, Matthew T., additional, Mitchell-Flack, Marisa, additional, Grillo, Isabella, additional, Bakogianni, Sofia, additional, Ndiaye-Lobry, Delphine, additional, Martín, Miguel Torres, additional, Guillamot, Maria, additional, Banh, Robert S., additional, Xu, Mingjiang, additional, Figueroa, Maria E., additional, Dickins, Ross A., additional, Abdel-Wahab, Omar, additional, Park, Christopher Y., additional, Tsirigos, Aristotelis, additional, Neel, Benjamin G., additional, and Aifantis, Iannis, additional

Published
2017
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189. BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Author

Valls, Ester, primary, Lobry, Camille, additional, Geng, Huimin, additional, Wang, Ling, additional, Cardenas, Mariano, additional, Rivas, Martín, additional, Cerchietti, Leandro, additional, Oh, Philmo, additional, Yang, Shao Ning, additional, Oswald, Erin, additional, Graham, Camille W., additional, Jiang, Yanwen, additional, Hatzi, Katerina, additional, Agirre, Xabier, additional, Perkey, Eric, additional, Li, Zhuoning, additional, Tam, Wayne, additional, Bhatt, Kamala, additional, Leonard, John P., additional, Zweidler-McKay, Patrick A., additional, Maillard, Ivan, additional, Elemento, Olivier, additional, Ci, Weimin, additional, Aifantis, Iannis, additional, and Melnick, Ari, additional

Published
2017
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190. Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

Author

Pan, Feng, primary, Wingo, Thomas S., additional, Zhao, Zhigang, additional, Gao, Rui, additional, Makishima, Hideki, additional, Qu, Guangbo, additional, Lin, Li, additional, Yu, Miao, additional, Ortega, Janice R., additional, Wang, Jiapeng, additional, Nazha, Aziz, additional, Chen, Li, additional, Yao, Bing, additional, Liu, Can, additional, Chen, Shi, additional, Weeks, Ophelia, additional, Ni, Hongyu, additional, Phillips, Brittany Lynn, additional, Huang, Suming, additional, Wang, Jianlong, additional, He, Chuan, additional, Li, Guo-Min, additional, Radivoyevitch, Tomas, additional, Aifantis, Iannis, additional, Maciejewski, Jaroslaw P., additional, Yang, Feng-Chun, additional, Jin, Peng, additional, and Xu, Mingjiang, additional

Published
2017
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191. Cardiac Myocyte KLF5 Regulates Adiposity via Alteration of Cardiac FGF21

Author

Pol, Christine J, primary, Pollak, Nina M, additional, Jurczak, Michael J, additional, Karagiannides, Iordanes, additional, Ntziachristos, Panagiotis, additional, Scerbo, Diego A, additional, Aifantis, Iannis, additional, Shulman, Gerald I, additional, Goldberg, Ira J, additional, and Drosatos, Konstantinos, additional

Published
2017
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193. Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Author

Witkowski, Matthew T., primary, Hu, Yifang, additional, Roberts, Kathryn G., additional, Boer, Judith M., additional, McKenzie, Mark D., additional, Liu, Grace J., additional, Le Grice, Oliver D., additional, Tremblay, Cedric S., additional, Ghisi, Margherita, additional, Willson, Tracy A., additional, Horstmann, Martin A., additional, Aifantis, Iannis, additional, Cimmino, Luisa, additional, Frietze, Seth, additional, den Boer, Monique L., additional, Mullighan, Charles G., additional, Smyth, Gordon K., additional, and Dickins, Ross A., additional

Published
2017
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197. MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis

Author

Aranda-Orgilles, Beatriz, primary, Saldaña-Meyer, Ricardo, additional, Wang, Eric, additional, Trompouki, Eirini, additional, Fassl, Anne, additional, Lau, Stephanie, additional, Mullenders, Jasper, additional, Rocha, Pedro P., additional, Raviram, Ramya, additional, Guillamot, María, additional, Sánchez-Díaz, María, additional, Wang, Kun, additional, Kayembe, Clarisse, additional, Zhang, Nan, additional, Amoasii, Leonela, additional, Choudhuri, Avik, additional, Skok, Jane A., additional, Schober, Markus, additional, Reinberg, Danny, additional, Sicinski, Piotr, additional, Schrewe, Heinrich, additional, Tsirigos, Aristotelis, additional, Zon, Leonard I., additional, and Aifantis, Iannis, additional

Published
2016
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200. RNA Splicing and Cancer

Author

Wang, Eric and Aifantis, Iannis

Abstract

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. Advances in next-generation RNA sequencing have revealed tumor-specific isoforms associated with these alterations, including the presence of neoantigens, which serve as potential immunotherapeutic targets. In this review, we discuss the various mechanisms by which cancer cells exploit RNA splicing to promote tumor growth and the current therapeutic landscape for splicing-based therapies.

Published
2020
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