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151. Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline.

Author

Graniel, Jacqueline V., Bisht, Kamlesh, Friedman, Ann, White, James, Perkey, Eric, Vanderbeck, Ashley, Moroz, Alina, Carrington, Léolène J., Brandstadter, Joshua D., Allen, Frederick, Shami, Adrienne Niederriter, Thomas, Peedikayil, Crayton, Aniela, Manzor, Mariel, Mychalowych, Anna, Chase, Jennifer, Hammoud, Saher S., Keegan, Catherine E., Maillard, Ivan, and Nandakumar, Jayakrishnan

Published
2022
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152. Acetylcholine‐synthesizing macrophages in subcutaneous fat are regulated by β2‐adrenergic signaling.

Author

Knights, Alexander J, Liu, Shanshan, Ma, Yingxu, Nudell, Victoria S, Perkey, Eric, Sorensen, Matthew J, Kennedy, Robert T, Maillard, Ivan, Ye, Li, Jun, Heejin, and Wu, Jun

Subjects
MACROPHAGES, FAT, ADIPOSE tissues, CHOLINERGIC receptors, FAT cells, ADRENERGIC receptors
Abstract

Non‐neuronal cholinergic signaling, mediated by acetylcholine, plays important roles in physiological processes including inflammation and immunity. Our group first discovered evidence of non‐neuronal cholinergic circuitry in adipose tissue, whereby immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis. Here, we reveal that macrophages are the cellular protagonists responsible for secreting acetylcholine to regulate thermogenic activation in subcutaneous fat, and we term these cells cholinergic adipose macrophages (ChAMs). An adaptive increase in ChAM abundance is evident following acute cold exposure, and macrophage‐specific deletion of choline acetyltransferase (ChAT), the enzyme for acetylcholine biosynthesis, impairs the cold‐induced thermogenic capacity of mice. Further, using pharmacological and genetic approaches, we show that ChAMs are regulated via adrenergic signaling, specifically through the β2 adrenergic receptor. These findings demonstrate that macrophages are an essential adipose tissue source of acetylcholine for the regulation of adaptive thermogenesis, and may be useful for therapeutic targeting in metabolic diseases. Synopsis: Immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis, yet the identity of these acetylcholine‐secreting cells is unclear. This study shows that a subpopulation of adipose macrophages—named cholinergic adipose macrophages (ChAMs)—is responsible for β2 adrenergic receptor‐dependent secretion of acetylcholine upon acute cold to stimulate thermogenesis in neighboring beige adipocytes within murine subcutaneous fat. A non‐neuronal cholinergic circuitry consisting of ChAMs and beige adipocytes in subcutaneous adipose tissue influences both thermogenic response to cold and energy homeostasis in mice.Loss of acetylcholine production in macrophages compromises the adaptive thermogenic capacity of subcutaneous fat.The β2 adrenergic receptor mediates cholinergic macrophage activation in subcutaneous fat after cold exposure. [ABSTRACT FROM AUTHOR]

Published
2021
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165. Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4+ T Cells in Graft-versus-Host Disease

Author

Chung, Jooho, primary, Radojcic, Vedran, additional, Perkey, Eric, additional, Parnell, Timothy J., additional, Niknafs, Yashar, additional, Jin, Xi, additional, Friedman, Ann, additional, Labrecque, Nathalie, additional, Blazar, Bruce R., additional, Brennan, Todd V., additional, Siebel, Christian W., additional, and Maillard, Ivan, additional

Published
2019
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166. B7-H4 expression in donor T cells and host cells negatively regulates acute graftversus- host disease lethality

Author

Saha, Asim, primary, Taylor, Patricia A., additional, Lees, Christopher J., additional, Panoskaltsis-Mortari, Angela, additional, Osborn, Mark J., additional, Feser, Colby J., additional, Thangavelu, Govindarajan, additional, Melchinger, Wolfgang, additional, Refaeli, Yosef, additional, Hill, Geoffrey R., additional, Munn, David H., additional, Serody, Jonathan S., additional, Maillard, Ivan, additional, Kreymborg, Katharina, additional, van den Brink, Marcel, additional, Dong, Chen, additional, Huang, Shuyu, additional, Zang, Xingxing, additional, Allison, James P, additional, Zeiser, Robert, additional, and Blazar, Bruce R., additional

Published
2019
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168. 1271

Author

Nafday, Abhinav, primary, Royan, Regina, additional, Maillard, Ivan, additional, Bixby, Dale, additional, Yentz, Sarah, additional, Cranford, James, additional, and Bassin, Benjamin, additional

Published
2019
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170. Pharmacologic Blockade of Notch/Delta-like Ligand 4 Signaling Protects from Gastrointestinal Acute Graft-Versus-Host Disease in Non-Human Primates

Author

Tkachev, Victor, primary, Kuhnert, Frank, additional, Furlan, Scott N, additional, Zheng, Hengqi, additional, Hunt, Daniel J, additional, Colonna, Lucrezia, additional, Carlson, Judith M, additional, Taraseviciute, Agne, additional, Panoskaltsis-Mortari, Angela, additional, Hoglund, Virginia, additional, Betz, Kayla, additional, Yu, Alison, additional, Blazar, Bruce R., additional, Carpenter, Steve, additional, Harari, Olivier, additional, Thurston, Gavin, additional, Maillard, Ivan, additional, and Kean, Leslie, additional

Published
2018
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172. 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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173. Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice

Author

Radojcic, Vedran, primary, Paz, Katelyn, additional, Chung, Jooho, additional, Du, Jing, additional, Perkey, Eric T., additional, Flynn, Ryan, additional, Ivcevic, Sanja, additional, Zaiken, Michael, additional, Friedman, Ann, additional, Yan, Minhong, additional, Pletneva, Maria A., additional, Sarantopoulos, Stefanie, additional, Siebel, Christian W., additional, Blazar, Bruce R., additional, and Maillard, Ivan, additional

Published
2018
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174. Notch signaling at the crossroads of innate and adaptive immunity.

Author

Vanderbeck, Ashley and Maillard, Ivan

Subjects
NATURAL immunity, INNATE lymphoid cells, CELL physiology, B cells, T cells, CD28 antigen
Abstract

Notch signaling is an evolutionarily conserved cell‐to‐cell signaling pathway that regulates cellular differentiation and function across multiple tissue types and developmental stages. In this review, we discuss our current understanding of Notch signaling in mammalian innate and adaptive immunity. The importance of Notch signaling is pervasive throughout the immune system, as it elicits lineage and context‐dependent effects in a wide repertoire of cells. Although regulation of binary cell fate decisions encompasses many of the functions first ascribed to Notch in the immune system, recent advances in the field have refined and expanded our view of the Notch pathway beyond this initial concept. From establishing T cell identity in the thymus to regulating mature T cell function in the periphery, the Notch pathway is an essential, recurring signal for the T cell lineage. Among B cells, Notch signaling is required for the development and maintenance of marginal zone B cells in the spleen. Emerging roles for Notch signaling in innate and innate‐like lineages such as classical dendritic cells and innate lymphoid cells are likewise coming into view. Lastly, we speculate on the molecular underpinnings that shape the activity and versatility of the Notch pathway. [ABSTRACT FROM AUTHOR]

Published
2021
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175. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial.

Author

Abella, Benjamin S., Jolkovsky, Eliana L., Biney, Barbara T., Uspal, Julie E., Hyman, Matthew C., Frank, Ian, Hensley, Scott E., Gill, Saar, Vogl, Dan T., Maillard, Ivan, Babushok, Daria V., Huang, Alexander C., Nasta, Sunita D., Walsh, Jennifer C., Wiletyo, E. Paul, Gimotty, Phyllis A., Milone, Michael C., and Amaravadi, Ravi K.

Published
2021
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176. Heat Shock Protein 70 (Hsp70) Suppresses RIP1-Dependent Apoptotic and Necroptotic Cascades.

Author

Srinivasan, Sharan R, Srinivasan, Sharan R, Cesa, Laura C, Li, Xiaokai, Julien, Olivier, Zhuang, Min, Shao, Hao, Chung, Jooho, Maillard, Ivan, Wells, James A, Duckett, Colin S, Gestwicki, Jason E, Srinivasan, Sharan R, Srinivasan, Sharan R, Cesa, Laura C, Li, Xiaokai, Julien, Olivier, Zhuang, Min, Shao, Hao, Chung, Jooho, Maillard, Ivan, Wells, James A, Duckett, Colin S, and Gestwicki, Jason E

Abstract

Hsp70 is a molecular chaperone that binds to "client" proteins and protects them from protein degradation. Hsp70 is essential for the survival of many cancer cells, but it is not yet clear which of its clients are involved. Using structurally distinct chemical inhibitors, we found that many of the well-known clients of the related chaperone, Hsp90, are not strikingly responsive to Hsp70 inhibition. Rather, Hsp70 appeared to be important for the stability of the RIP1 (RIPK1) regulators: cIAP1/2 (BIRC1 and BIRC3), XIAP, and cFLIPS/L (CFLAR). These results suggest that Hsp70 limits apoptosis and necroptosis pathways downstream of RIP1. Consistent with this model, MDA-MB-231 breast cancer cells treated with Hsp70 inhibitors underwent apoptosis, while cotreatment with z-VAD.fmk switched the cell death pathway to necroptosis. In addition, cell death in response to Hsp70 inhibitors was strongly suppressed by RIP1 knockdown or inhibitors. Thus, these data indicate that Hsp70 plays a previously unrecognized and important role in suppressing RIP1 activity.Implications: These findings clarify the role of Hsp70 in prosurvival signaling and suggest IAPs as potential new biomarkers for Hsp70 inhibition. Mol Cancer Res; 16(1); 58-68. ©2017 AACR.

Published
2018

177. Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

Author

Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Division of Comparative Medicine, Fox, James G, Wang, Yiwei, Huang, Dan, Chen, Kai-Yuan, Cui, Min, Wang, Weihuan, Huang, Xiaoran, Awadellah, Amad, Li, Qing, Friedman, Ann, Xin, William W., Di Martino, Luca, Cominelli, Fabio, Miron, Alex, Chan, Ricky, Fox, James G., Xu, Yan, Shen, Xiling, Kalady, Mathew F., Markowitz, Sanford, Maillard, Ivan, Lowe, John B., Xin, Wei, Zhou, Lan, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Division of Comparative Medicine, Fox, James G, Wang, Yiwei, Huang, Dan, Chen, Kai-Yuan, Cui, Min, Wang, Weihuan, Huang, Xiaoran, Awadellah, Amad, Li, Qing, Friedman, Ann, Xin, William W., Di Martino, Luca, Cominelli, Fabio, Miron, Alex, Chan, Ricky, Fox, James G., Xu, Yan, Shen, Xiling, Kalady, Mathew F., Markowitz, Sanford, Maillard, Ivan, Lowe, John B., Xin, Wei, and Zhou, Lan

Abstract

De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%–13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. Methods FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). Results Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylatio

Published
2018

178. Cutting Edge: Notch Signaling Promotes the Plasticity of Group-2 Innate Lymphoid Cells

Author

Zhang, Kangning, Xu, Xingyuan, Pasha, Muhammad Asghar, Siebel, Christian W, Costello, Angelica, Haczku, Angela, MacNamara, Katherine, Liang, Tingbo, Zhu, Jinfang, Bhandoola, Avinash, Maillard, Ivan, and Yang, Qi

Subjects
Notch, Nuclear Receptor Subfamily 1, Member 3, Immunology, Inbred C57BL, Vaccine Related, Mice, Group F, Biodefense, Receptors, Animals, Innate, 2.1 Biological and endogenous factors, Cell Lineage, Lymphocytes, Aetiology, Inflammation, Interleukin-13, Prevention, Inflammatory and immune system, Pyroglyphidae, Interleukin-17, Immunity, Emerging Infectious Diseases, Cytokines, Signal Transduction
Abstract

The mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, plastic inflammatory ILC2 (iILC2) can coproduce both type-2 cytokines and the ILC3-characteristic cytokine, IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. In this study we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of mature ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc expression and elicited dual IL-13/IL-17 production, converting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly proinflammatory innate lymphocytes.

Published
2017

179. Notch signaling promotes the plasticity of group-2 innate lymphoid cells

Author

Zhang, Kangning, Xu, Xingyuan, Pasha, Muhammad Asghar, Siebel, Christian W., Costello, Angelica, Haczku, Angela, MacNamara, Katherine, Liang, Tingbo, Zhu, Jinfang, Bhandoola, Avinash, Maillard, Ivan, and Yang, Qi

Subjects
Inflammation, Interleukin-13, Receptors, Notch, Interleukin-17, Pyroglyphidae, Nuclear Receptor Subfamily 1, Group F, Member 3, Article, Immunity, Innate, Mice, Inbred C57BL, Mice, Animals, Cytokines, Cell Lineage, Lymphocytes, Signal Transduction
Abstract

Mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, “plastic” inflammatory ILC2 (iILC2) can co-produce both type-2 cytokines and also the ILC3-characteristic cytokine IL-17. Mechanisms that elicit this lineage plasticity, and the importance in health and disease, remain unclear. Here we show that iILC2 are potent inducers of airway inflammation in response to acute house dust mite challenge. We find that Notch signaling induces lineage plasticity of mature ILC2 and drives the conversion of nILC2 into iILC2. Acute blockade of Notch signaling abolished functional iILC2, but not nILC2, in vivo. Exposure of isolated nILC2 to Notch ligands induced Rorc expression and elicited dual IL-13/IL-17 production, converting nILC2 into iILC2. Together these results reveal a novel role for Notch signaling in eliciting ILC2 plasticity and driving the emergence of highly pro-inflammatory innate lymphocytes.

Published
2017

180. Inflammation keeps old mice healthy

Author

Maillard, Ivan and Saltiel, Alan R.

Subjects
Inflammation -- Physiological aspects -- Research -- Influence, Insulin resistance -- Physiological aspects -- Analysis, Cardiovascular diseases -- Research -- Care and treatment -- Complications and side effects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Immune cells called regulatory T cells accumulate in fat during ageing. The anti-inflammatory activity of these cells worsens age-associated defects in metabolism, in contrast to its effect in obesity. See [...]

Published
2015

181. Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner

Author

McDonald-Hyman, Cameron, Flynn, Ryan, Panoskaltsis-Mortari, Angela, Peterson, Nicholas, MacDonald, Kelli P.A., Hill, Geoffrey R., Luznik, Leo, Serody, Jonathan S., Murphy, William J., Maillard, Ivan, Munn, David H., Turka, Laurence A., Koreth, John, Cutler, Corey S., Soiffer, Robert J., Antin, Joseph H., Ritz, Jerome, and Blazar, Bruce R.

Published
2016
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182. One-two punch injury to tolerance mechanisms in graft-versus-host disease.

Author

Carrington, Léolène J. and Maillard, Ivan

Subjects
*ANIMAL experimentation, *ANTIGENS, *COMPARATIVE studies, *GRAFT versus host disease, *HEMATOPOIETIC stem cell transplantation, *HOMOGRAFTS, *IMMUNITY, *IMMUNOLOGICAL tolerance, *LYMPH nodes, *RESEARCH methodology, *MEDICAL cooperation, *MICE, *RESEARCH, *EVALUATION research
Abstract

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation that resembles autoimmunity, with unclear pathogenesis and few effective therapeutic options. In this issue of the JCI, Dertschnig et al. used mouse models to investigate the basis of T cell autoreactivity following GVHD. Notably, GVHD caused irreversible damage to a population of tolerogenic stromal cells that display peripheral tissue-restricted antigens in lymph nodes, which impaired their capacity to purge and suppress autoreactive T cells. Together with damage to central tolerance mechanisms in the thymus, these findings outline a critical one-two punch injury that profoundly disrupts immune tolerance in this devastating disease. [ABSTRACT FROM AUTHOR]

Published
2020
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183. Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development

Author

Wang, Qing, primary, Yan, Ran, additional, Pinnell, Nancy, additional, McCarter, Anna C., additional, Oh, Yeonjoo, additional, Liu, Yiran, additional, Sha, Cher, additional, Garber, Noah F., additional, Chen, Yitong, additional, Wu, Qingqing, additional, Ku, Chia-Jui, additional, Tran, Ivy, additional, Serna Alarcon, Amparo, additional, Kuick, Rork, additional, Engel, James Douglas, additional, Maillard, Ivan, additional, Cierpicki, Tomasz, additional, and Chiang, Mark Y., additional

Published
2018
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187. MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis

Author

Trissal, Maria C., primary, Wong, Terrence N., additional, Yao, Juo-Chin, additional, Ramaswamy, Rahul, additional, Kuo, Iris, additional, Baty, Jack, additional, Sun, Yaping, additional, Jih, Gloria, additional, Parikh, Nishi, additional, Berrien-Elliott, Melissa M., additional, Fehniger, Todd A., additional, Ley, Timothy J., additional, Maillard, Ivan, additional, Reddy, Pavan R., additional, and Link, Daniel C., additional

Published
2018
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188. An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling

Author

Jun, Heejin, primary, Yu, Hui, additional, Gong, Jianke, additional, Jiang, Juan, additional, Qiao, Xiaona, additional, Perkey, Eric, additional, Kim, Dong-il, additional, Emont, Margo P., additional, Zestos, Alexander G., additional, Cho, Jung-Sun, additional, Liu, Jianfeng, additional, Kennedy, Robert T., additional, Maillard, Ivan, additional, Xu, X. Z. Shawn, additional, and Wu, Jun, additional

Published
2018
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192. An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD

Author

Poe, Jonathan C., primary, Jia, Wei, additional, Su, Hsuan, additional, Anand, Sarah, additional, Rose, Jeremy J., additional, Tata, Prasanthi V., additional, Suthers, Amy N., additional, Jones, Corbin D., additional, Kuan, Pei Fen, additional, Vincent, Benjamin G., additional, Serody, Jonathan S., additional, Horwitz, Mitchell E., additional, Ho, Vincent T., additional, Pavletic, Steven Z., additional, Hakim, Frances T., additional, Owzar, Kouros, additional, Zhang, Dadong, additional, Blazar, Bruce R., additional, Siebel, Christian W., additional, Chao, Nelson J., additional, Maillard, Ivan, additional, and Sarantopoulos, Stefanie, additional

Published
2017
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193. Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Author

Thangavelu, Govindarajan, Wang, Chao, Loschi, Michael, Saha, Asim, Osborn, Mark J., Furlan, Scott N., Aoyama, Kazutoshi, McDonald-Hyman, Cameron, Aguilar, Ethan G., Janesick, Amanda S., Chandraratna, Roshantha A., Refaeli, Yosef, Panoskaltsis-Mortari, Angela, MacDonald, Kelli P., Hill, Geoffrey R., Zeiser, Robert, Maillard, Ivan, Serody, Jonathan S., Murphy, William J., Munn, David H., Blumberg, Bruce, Brown, Chrysothemis, Kuchroo, Vijay, Kean, Leslie S., Hippen, Keli L., Noelle, Randolph J., and Blazar, Bruce R.

Abstract

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3− T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

Published
2021
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194. 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

195. Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

Author

Wang, Yiwei, Huang, Dan, Chen, Kai-Yuan, Cui, Min, Wang, Weihuan, Huang, Xiaoran, Awadellah, Amad, Li, Qing, Friedman, Ann, Xin, William W., Di Martino, Luca, Cominelli, Fabio, Miron, Alex, Chan, Ricky, Fox, James G., Xu, Yan, Shen, Xiling, Kalady, Mathew F., Markowitz, Sanford, Maillard, Ivan, Lowe, John B., Xin, Wei, Zhou, Lan, Fox, James G, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Division of Comparative Medicine, and Fox, James G

Subjects
0301 basic medicine, Male, Colorectal cancer, Carcinogenesis, medicine.disease_cause, Cecum, Feces, Mice, Receptor, Notch2, HES1, Intestinal Mucosa, Receptor, Notch1, Fucosylation, Bone Marrow Transplantation, Aged, 80 and over, Mice, Knockout, Gastroenterology, Ketone Oxidoreductases, Middle Aged, Colitis, medicine.anatomical_structure, Colonic Neoplasms, Adenocarcinoma, Cytokines, Female, Signal Transduction, Adult, Colon, Biology, MLH1, Article, Permeability, 03 medical and health sciences, Young Adult, Guanosine Diphosphate Fucose, medicine, Animals, Humans, RNA, Messenger, Aged, Cell Proliferation, Fucose, Hepatology, medicine.disease, Gastrointestinal Microbiome, 030104 developmental biology, Cancer research, Transcription Factor HES-1, Carbohydrate Epimerases
Abstract

Background & Aims De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%–13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. Methods FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). Results Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. Conclusions In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.

Published
2016

196. CD8+T cells contribute to survival in patients with COVID-19 and hematologic cancer

Author

Bange, Erin M., Han, Nicholas A., Wileyto, Paul, Kim, Justin Y., Gouma, Sigrid, Robinson, James, Greenplate, Allison R., Hwee, Madeline A., Porterfield, Florence, Owoyemi, Olutosin, Naik, Karan, Zheng, Cathy, Galantino, Michael, Weisman, Ariel R., Ittner, Caroline A. G., Kugler, Emily M., Baxter, Amy E., Oniyide, Olutwatosin, Agyekum, Roseline S., Dunn, Thomas G., Jones, Tiffanie K., Giannini, Heather M., Weirick, Madison E., McAllister, Christopher M., Babady, N. Esther, Kumar, Anita, Widman, Adam J., DeWolf, Susan, Boutemine, Sawsan R., Roberts, Charlotte, Budzik, Krista R., Tollett, Susan, Wright, Carla, Perloff, Tara, Sun, Lova, Mathew, Divij, Giles, Josephine R., Oldridge, Derek A., Wu, Jennifer E., Alanio, Cécile, Adamski, Sharon, Garfall, Alfred L., Vella, Laura A., Kerr, Samuel J., Cohen, Justine V., Oyer, Randall A., Massa, Ryan, Maillard, Ivan P., Maxwell, Kara N., Reilly, John P., Maslak, Peter G., Vonderheide, Robert H., Wolchok, Jedd D., Hensley, Scott E., Wherry, E. John, Meyer, Nuala J., DeMichele, Angela M., Vardhana, Santosha A., Mamtani, Ronac, and Huang, Alexander C.

Abstract

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses.

Published
2021
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197. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease

Author

van Rhee, Frits, Oksenhendler, Eric, Srkalovic, Gordan, Voorhees, Peter, Lim, Megan, Dispenzieri, Angela, Ide, Makoto, Parente, Sophia, Schey, Stephen, Streetly, Matthew, Wong, Raymond, Wu, David, Maillard, Ivan, Brandstadter, Joshua, Munshi, Nikhil, Bowne, Wilbur, Elenitoba-Johnson, Kojo S., Fössa, Alexander, Lechowicz, Mary Jo, Chandrakasan, Shanmuganathan, Pierson, Sheila K., Greenway, Amy, Nasta, Sunita, Yoshizaki, Kazuyuki, Kurzrock, Razelle, Uldrick, Thomas S., Casper, Corey, Chadburn, Amy, and Fajgenbaum, David C.

Abstract

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Published
2020
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199. Abstract 1373: The role of the ASH1L SET domain in leukemogenesis

Author

Rogawski, David, primary, Miao, Hongzhi, additional, Kempinska, Katarzyna, additional, Chen, Lili, additional, Chase, Jen, additional, Friedman, Ann, additional, Yan, Xiaomei, additional, Nishioka, Kenichi, additional, Huang, Gang, additional, Ernst, Patricia, additional, Muntean, Andy, additional, Maillard, Ivan, additional, Cierpicki, Tomasz, additional, and Grembecka, Jolanta, additional

Published
2017
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