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Julie L Mitchell, Amara Seng, Thomas M Yankee
The Ikaros family of transcription factors is essential for normal T cell development, but their expression pattern in human thymocytes remains poorly defined. Our goal is to determine how protein levels of Ikaros, Helios, and Aiolos change as human thymocytes progress through the positive selection and lineage commitment stages. To accomplish this goal, we used multi-parameter flow cytometry to define the populations in which positive selection and lineage commitment are most likely to occur. After human thymocytes express CD3 and receive positive selection signals, the cells down-regulate expression of CD4 to become transitional single positive (TSP) CD8(+) thymocytes...
August 9, 2016: Immunology
Takumi Ito, Hiroshi Handa
Thalidomide was first developed as a sedative around 60 years ago, but exhibited teratogenicity, leading to serious defects such as limb deformities. Nevertheless, thalidomide is now recognized as a therapeutic drug for the treatment of Hansen's disease and myeloma. Immunomodulatory drugs (IMiDs), a new class of anti-cancer drug derived from thalidomide, have also been developed and exert potent anti-cancer effects. Although the molecular mechanism of thalidomide and IMiDs remained unclear for a long time, cereblon, a substrate receptor of the CRL4 E3 ubiquitin ligase was identified as a primary direct target by a new affinity technique...
September 2016: International Journal of Hematology
Takumi Ito, Hideki Ando, Hiroshi Handa
Half a century ago, the sedative thalidomide caused a serious drug disaster because of its teratogenicity and was withdrawn from the market. However, thalidomide, which has returned to the market, is now used for the treatment of leprosy and multiple myeloma (MM) under strict control. The mechanism of thalidomide action had been a long-standing question. We developed a new affinity bead technology and identified cereblon (CRBN) as a thalidomide-binding protein. We found that CRBN functions as a substrate receptor of an E3 cullin-Ring ligase complex 4 (CRL4) and is a primary target of thalidomide teratogenicity...
May 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Qinqin Xu, Yue-xian Hou, Paul Langlais, Patrick Erickson, James Zhu, Chang-Xin Shi, Moulun Luo, Yuanxiao Zhu, Ye Xu, Lawrence J Mandarino, Keith Stewart, Xiu-bao Chang
BACKGROUND: Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity...
2016: BMC Cancer
Pavel Otáhal, Dana Průková, Vlastimil Král, Milan Fabry, Petra Vočková, Lucie Latečková, Marek Trněný, Pavel Klener
Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype...
April 2016: Oncoimmunology
Michel Jourdan, Maïlys Cren, Peter Schafer, Nicolas Robert, Christophe Duperray, Laure Vincent, Patrice Ceballos, Guillaume Cartron, Jean-François Rossi, Jérôme Moreaux, Rajesh Chopra, Bernard Klein
Thalidomide, lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma. However, their effects on plasma cells, the healthy counterpart of myeloma cells, are unknown. Here, we investigated lenalidomide effects on normal human plasma cell generation using an in vitro model. Lenalidomide inhibited the generation of pre-plasmablasts and early plasma cells, while it moderately affected plasmablast production. It also reduced the expression level of Ikaros, Aiolos, and IRF4 transcription factors, in plasmablasts and early plasma cells...
May 10, 2016: Oncotarget
Emily Rychak, Derek Mendy, Tao Shi, Yuhong Ning, Jim Leisten, Ling Lu, Karen Miller, Rama K Narla, Robert Z Orlowski, Heather K Raymon, Chad C Bjorklund, Anjan Thakurta, Anita K Gandhi, Brian E Cathers, Rajesh Chopra, Thomas O Daniel, Antonia Lopez-Girona
Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines...
March 2016: British Journal of Haematology
Georg Petzold, Eric S Fischer, Nicolas H Thomä
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1α (CK1α), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively...
April 7, 2016: Nature
K-H Hung, S-T Su, C-Y Chen, P-H Hsu, S-Y Huang, W-J Wu, M-J M Chen, H-Y Chen, P-C Wu, F-R Lin, M-D Tsai, K-I Lin
The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes...
July 2016: Cell Death and Differentiation
Julie L Mitchell, Amara Seng, Thomas M Yankee
In human T cell development, the mechanisms that regulate cell fate decisions after TCRβ expression remain unclear. We defined the stages of T cell development that flank TCRβ expression and found distinct patterns of human T cell development. In half the subjects, T cell development progressed from the CD4(-)CD8(-) double-negative stage to the CD4(+)CD8(+) double-positive (DP) stage through an immature single-positive (ISP) CD4(+) intermediate. However, in some patients, CD4 and CD8 were expressed simultaneously and the ISP population was small...
April 2016: Immunologic Research
Xinze Cai, Xudong Liu, Shuyan Du, Xiaoxue Xu, Ang Liu, Xin Ge, Ying Qiao, Yi Jiang
Genetic studies demonstrate that the Aiolos polymorphisms contribute to the susceptibility to autoimmune diseases. The purpose of the study was to investigate the Aiolos expression in lymphocytes and monocytes in the peripheral blood from patients with SLE and RA, and to explore the correlation between Aiolos expression in cell subsets and laboratory measurements. Peripheral blood mononuclear cells (PBMC) from 32 patients with SLE, 35 patients with RA, and 37 healthy controls were purified. Aiolos expression in PBMC subsets was examined by flow cytometry...
February 2016: Biochemical Genetics
Cinzia Fionda, Maria Pia Abruzzese, Alessandra Zingoni, Francesca Cecere, Elisabetta Vulpis, Giovanna Peruzzi, Alessandra Soriani, Rosa Molfetta, Rossella Paolini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Angela Santoni, Marco Cippitelli
Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms...
September 15, 2015: Oncotarget
Carine Bouffi, Andrey V Kartashov, Kaila L Schollaert, Xiaoting Chen, W Clark Bacon, Matthew T Weirauch, Artem Barski, Patricia C Fulkerson
The production of mature eosinophils (Eos) is a tightly orchestrated process with the aim to sustain normal Eos levels in tissues while also maintaining low numbers of these complex and sensitive cells in the blood. To identify regulators of homeostatic eosinophilopoiesis in mice, we took a global approach to identify genome-wide transcriptome and epigenome changes that occur during homeostasis at critical developmental stages, including Eos-lineage commitment and lineage maturation. Our analyses revealed a markedly greater number of transcriptome alterations associated with Eos maturation (1199 genes) than with Eos-lineage commitment (490 genes), highlighting the greater transcriptional investment necessary for differentiation...
September 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Jonas Bystrom, Taher E Taher, M Sherwan Muhyaddin, Felix I Clanchy, Pamela Mangat, Ali S Jawad, Richard O Williams, Rizgar A Mageed
Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions...
2015: Mediators of Inflammation
Hidehiko Kikuchi, Masami Nakayama, Futoshi Kuribayashi, Hitomi Mimuro, Shinobu Imajoh-Ohmi, Hideki Nishitoh, Yasunari Takami, Tatsuo Nakayama
The transcription factor paired box gene 5 (Pax5) is essential for B cell development. In this study, complementation analyses in Pax5-deficient DT40 cells showed that three Pax5 isoforms Pax5A, Pax5B and Pax5BΔEx8 (another spliced isoform of Pax5B lacking exon 8) exhibit distinct roles in transcriptional regulation of six B cell development-related genes (activation-induced cytidine deaminase, Aiolos, BTB and CNC homology 2, B cell lymphoma-6, early B cell factor 1, origin binding factor-1 genes), transcriptions of which are remarkably down-regulated by Pax5-deficiency...
July 2015: Microbiology and Immunology
Patrick R Hagner, Hon-Wah Man, Celia Fontanillo, Maria Wang, Suzana Couto, Mike Breider, Chad Bjorklund, Courtney G Havens, Gang Lu, Emily Rychak, Heather Raymon, Rama Krishna Narla, Leo Barnes, Gody Khambatta, Hsiling Chiu, Jolanta Kosek, Jian Kang, Michael D Amantangelo, Michelle Waldman, Antonia Lopez-Girona, Ti Cai, Michael Pourdehnad, Matthew Trotter, Thomas O Daniel, Peter H Schafer, Anke Klippel, Anjan Thakurta, Rajesh Chopra, Anita K Gandhi
Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects...
August 6, 2015: Blood
Kartik Sehgal, Rituparna Das, Lin Zhang, Rakesh Verma, Yanhong Deng, Mehmet Kocoglu, Juan Vasquez, Srinivas Koduru, Yan Ren, Maria Wang, Suzana Couto, Mike Breider, Donna Hansel, Stuart Seropian, Dennis Cooper, Anjan Thakurta, Xiaopan Yao, Kavita M Dhodapkar, Madhav V Dhodapkar
In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events...
June 25, 2015: Blood
Jan Krönke, Slater N Hurst, Benjamin L Ebert
Lenalidomide and its analogs, thalidomide and pomalidomide, specifically inhibit growth of mature B-cell lymphomas, including multiple myeloma, and induce interleukin-2 (IL-2) release from T cells. We recently found that this results from activation of the CRBN-CRL4 E3 ubiquitin ligase to degrade the lymphoid transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos).
2014: Oncoimmunology
Ran Wang, Gang Guo, Hao Li, Xiangxin Li, Yuan Yu, Dong Li
The aim of the present study was to elucidate the molecular mechanism of Aiolos in the regulation of B‑cell leukaemia. A lentiviral system was used for overexpression of the Aiolos gene in Nalm‑6 cells to determine the effects of Aiolos on proliferation, apoptosis and the cell cycle. The expression and activation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and Akt were also investigated. Upregulation of Aiolos inhibited cell growth and arrested an increased number of Nalm‑6 cells at the G0/G1 phase...
May 2015: Molecular Medicine Reports
Yong Zhuang, Yuanyuan Lu, Dong Li, Nianzheng Sun, Xiuli Ju
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to T-cell lineage. T-ALL accounts for ~15% of pediatric ALL cases and is prone to early relapse. With new and improved treatment protocols, the prognosis of T-ALL has improved particularly in children; however, the outcome of relapsed T-ALL cases remains poor. The AIOLOS gene is necessary to control lymphocyte differentiation and may be a potential target of T-ALL therapy. In the present study, Jurkat cells were divided into three groups: untransfected (UT) control, lentiviral vector control (Lenti-Mock) and AIOLOS-overexpressing (Lenti-AIOLOS) groups...
March 2015: Oncology Reports
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