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https://www.readbyqxmd.com/read/28052520/ikaros-expression-in-distinct-bone-marrow-cell-populations-as-a-candidate-biomarker-for-outcome-with-lenalidomide-dexamethasone-therapy-in-multiple-myeloma
#1
Arnold Bolomsky, Wolfgang Hübl, Stefano Spada, Ercan Müldür, Karin Schlangen, Daniel Heintel, Alberto Rocci, Adalbert Weißmann, Veronique Fritz, Martin Willheim, Niklas Zojer, Antonio Palumbo, Heinz Ludwig
Immunomodulatory drugs (IMiDs) are a cornerstone in the treatment of multiple myeloma (MM), but specific markers to predict outcome are still missing. Recent work pointed to a prognostic role for IMiD target genes (e.g. CRBN). Moreover, indirect activity of IMiDs on immune cells correlated with outcome, raising the possibility that cell populations in the bone marrow (BM) microenvironment could serve as biomarkers. We therefore analysed gene expression levels of six IMiD target genes in whole BM samples of 44 myeloma patients treated with lenalidomide-dexamethasone...
January 4, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28028022/multiple-myeloma-cells-capacity-to-decompose-h2o2-determines-lenalidomide-sensitivity
#2
Sinto Sebastian, Yuan X Zhu, Esteban Braggio, Chang-Xin Shi, Sonali C Panchabhai, Scott A Van Wier, Greg J Ahmann, Marta Chesi, P Leif Bergsagel, A Keith Stewart, Rafael Fonseca
Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (CRBN) is an essential requirement for IMiD action, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H2O2 decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and associated cytotoxicity...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28024514/-advances-of-crbn-in-immunomodulatory-drugs-for-multiple-myeloma-review
#3
Ran An, Jian Hou
Multiple myeloma is a plasma cell malignant clone proliferation diseases and has been remained incurable. In the resent years, the widespread application of immunomodulatory drugs (IMiD) have made a great progress in the treatment of multiple myeloma, greatly improved the complete remission rate and prolonged the overall survival of MM patients. According to recent researches, CRBN (cereblon) plays an important role in mediating anti-myeloma effects of IMiD, and its expression correlated with the effect of IMiD treatment and the prognosis of multiple myeloma...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28017969/ikzf1-expression-is-a-prognostic-marker-in-newly-diagnosed-standard-risk-multiple-myeloma-treated-with-lenalidomide-and-intensive-chemotherapy-a-study-of-the-german-myeloma-study-group-dsmm
#4
J Krönke, F Kuchenbauer, M Kull, V Teleanu, L Bullinger, D Bunjes, A Greiner, S Kolmus, S Köpff, M Schreder, L-O Mügge, C Straka, M Engelhardt, H Döhner, H Einsele, F Bassermann, R Bargou, S Knop, C Langer
Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth-inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from sixty patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27751757/genomic-and-in-silico-analyses-of-crbn-gene-and-thalidomide-embryopathy-in-humans
#5
Fernanda Sales Luiz Vianna, Thayne Woycinck Kowalski, Luciana Tovo-Rodrigues, Alice Tagliani-Ribeiro, Bibiane Armiliato Godoy, Lucas Rosa Fraga, Maria Teresa Vieira Sanseverino, Mara Helena Hutz, Lavínia Schuler-Faccini
Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a thalidomide target protein encoded by CRBN gene, have helped to understand thalidomide therapeutic and teratogenic properties. We sequenced CRBN-thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group (p=0...
October 14, 2016: Reproductive Toxicology
https://www.readbyqxmd.com/read/27702999/ohgata-the-single-drosophila-ortholog-of-human-cereblon-regulates-insulin-signaling-dependent-organismic-growth
#6
Satoru Wakabayashi, Naoya Sawamura, André Voelzmann, Meike Broemer, Toru Asahi, Michael Hoch
Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning, and memory formation, and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo, however, are still scarce...
November 25, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27618360/prognostic-significance-of-cereblon-expression-in-patients-with-multiple-myeloma
#7
Jelena Bila, Aleksandra Sretenovic, Jelena Jelicic, Natasa Tosic, Irena Glumac, Marija Dencic Fekete, Darko Antic, Milena Todorovic Balint, Olivera Markovic, Zoran Milojevic, Milica Radojkovic, Goran Trajkovic, Mila Puric, Sonja Pavlovic, Biljana Mihaljevic
BACKGROUND: To personalize the treatment approach for patients with multiple myeloma (MM), molecular markers such as cereblon (CRBN) are currently the focus of investigation. The aim of the present study was to test the prognostic significance of CRBN expression in MM patients ineligible for autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: The data from 92 previously untreated patients were analyzed. The distribution according to the International Staging System score was 26...
August 10, 2016: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/27492707/the-molecular-mechanism-of-thalidomide-analogs-in-hematologic-malignancies
#8
REVIEW
Stefanie Lindner, Jan Krönke
Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-α and increase interleukin-2 (IL-2) and interferon-γ release from T cells...
December 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27468689/cereblon-negatively-regulates-tlr4-signaling-through-the-attenuation-of-ubiquitination-of-traf6
#9
Yoon Min, Sae Mi Wi, Jung-Ah Kang, Taewoo Yang, Chul-Seung Park, Sung-Gyoo Park, Sungkwon Chung, Jae-Hyuck Shim, Eunyoung Chun, Ki-Young Lee
Cereblon (CRBN) is a substrate receptor protein for the CRL4A E3 ubiquitin ligase complex. In this study, we report on a new regulatory role of CRBN in TLR4 signaling. CRBN overexpression leads to suppression of NF-κB activation and production of pro-inflammatory cytokines including IL-6 and IL-1β in response to TLR4 stimulation. Biochemical studies revealed interactions between CRBN and TAK1, and TRAF6 proteins. The interaction between CRBN and TAK1 did not affect the association of the TAB1 and TAB2 proteins, which have pivotal roles in the activation of TAK1, whereas the CRBN-TRAF6 interaction critically affected ubiquitination of TRAF6 and TAB2...
2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27460676/cereblon-and-its-downstream-substrates-as-molecular-targets-of-immunomodulatory-drugs
#10
REVIEW
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
https://www.readbyqxmd.com/read/27458004/targeted-sequencing-of-refractory-myeloma-reveals-a-high-incidence-of-mutations-in-crbn-and-ras-pathway-genes
#11
K Martin Kortüm, Elias K Mai, Nur H Hanafiah, Chang-Xi Shi, Yuan-Xiao Zhu, Laura Bruins, Santiago Barrio, Patrick Jedlowski, Maximilian Merz, Jing Xu, Robert A Stewart, Mindaugas Andrulis, Anna Jauch, Jens Hillengass, Hartmut Goldschmidt, P Leif Bergsagel, Esteban Braggio, A Keith Stewart, Marc S Raab
In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy...
September 1, 2016: Blood
https://www.readbyqxmd.com/read/27439875/epigenetic-regulation-of-kcna3-encoding-kv1-3-potassium-channel-by-cereblon-contributes-to-regulation-of-cd4-t-cell-activation
#12
Jung-Ah Kang, Sang-Heon Park, Sang Phil Jeong, Min-Hee Han, Cho-Rong Lee, Kwang Min Lee, Namhee Kim, Mi-Ryoung Song, Murim Choi, Michael Ye, Guhung Jung, Won-Woo Lee, Soo Hyun Eom, Chul-Seung Park, Sung-Gyoo Park
The role of cereblon (CRBN) in T cells is not well understood. We generated mice with a deletion in Crbn and found cereblon to be an important antagonist of T-cell activation. In mice lacking CRBN, CD4(+) T cells show increased activation and IL-2 production on T-cell receptor stimulation, ultimately resulting in increased potassium flux and calcium-mediated signaling. CRBN restricts T-cell activation via epigenetic modification of Kcna3, which encodes the Kv1.3 potassium channel required for robust calcium influx in T cells...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27417535/mitochondrial-cereblon-functions-as-a-lon-type-protease
#13
Kosuke Kataoka, China Nakamura, Toru Asahi, Naoya Sawamura
Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix, and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. However, whether CRBN has Lon protease-like function remains unknown. Here, we determined if CRBN has a protective function against oxidative stress, similar to Lon protease...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27365142/thalidomide-based-induction-regimens-are-as-effective-as-bortezomib-based-regimens-in-elderly-patients-with-multiple-myeloma-with-cereblon-expression
#14
Sung-Hoon Jung, Hyun-Jung Choi, Myung-Geun Shin, Seung-Shin Lee, Eu Chang Hwang, Tae-Young Jung, Min-Seok Cho, Deok-Hwan Yang, Jae-Sook Ahn, Yeo-Kyeoung Kim, Hyeoung-Joon Kim, Je-Jung Lee
Cereblon (CRBN) has been identified as a primary target of immunomodulatory drugs and is considered a biomarker for the prediction of outcomes after thalidomide- or lenalidomide-based treatments. In this study, we evaluated CRBN expression in bone marrow (BM) tissue at diagnosis and investigated the relationship between CRBN expression and treatment outcomes after thalidomide- or bortezomib-based front-line therapies in 89 elderly patients with multiple myeloma (MM). CRBN expression at the time of diagnosis was evaluated with immunohistochemical (IHC) staining for myeloma cells in paraffin wax-embedded BM tissue...
October 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27343276/a-ubiquitin-independent-function-of-crbn-mediates-the-response-to-imids
#15
(no author information available yet)
CRBN promotes CD147-MCT1-mediated antitumor activity in response to IMiDs.
August 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27343012/cereblon-in-health-and-disease
#16
REVIEW
Hyoung Kyu Kim, Tae Hee Ko, Bayalagmaa Nyamaa, Sung Ryul Lee, Nari Kim, Kyung Soo Ko, Byoung Doo Rhee, Chul-Seung Park, Bernd Nilius, Jin Han
Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that has been linked to autosomal recessive non-syndromic mental retardation. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling...
August 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27338790/a-novel-cereblon-modulator-recruits-gspt1-to-the-crl4-crbn-ubiquitin-ligase
#17
Mary E Matyskiela, Gang Lu, Takumi Ito, Barbra Pagarigan, Chin-Chun Lu, Karen Miller, Wei Fang, Nai-Yu Wang, Derek Nguyen, Jack Houston, Gilles Carmel, Tam Tran, Mariko Riley, Lyn'Al Nosaka, Gabriel C Lander, Svetlana Gaidarova, Shuichan Xu, Alexander L Ruchelman, Hiroshi Handa, James Carmichael, Thomas O Daniel, Brian E Cathers, Antonia Lopez-Girona, Philip P Chamberlain
Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism...
14, 2016: Nature
https://www.readbyqxmd.com/read/27329811/nuclear-cereblon-modulates-transcriptional-activity-of-ikaros-and-regulates-its-downstream-target-enkephalin-in-human-neuroblastoma-cells
#18
Takeyoshi Wada, Toru Asahi, Naoya Sawamura
The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization...
August 26, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27325702/amyloid-precursor-protein-app-may-act-as-a-substrate-and-a-recognition-unit-for-crl4crbn-and-stub1-e3-ligases-facilitating-ubiquitination-of-proteins-involved-in-presynaptic-functions-and-neurodegeneration
#19
Dolores Del Prete, Richard C Rice, Anjali M Rajadhyaksha, Luciano D'Adamio
The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27294876/immunomodulatory-drugs-disrupt-the-cereblon-cd147-mct1-axis-to-exert-antitumor-activity-and-teratogenicity
#20
Ruth Eichner, Michael Heider, Vanesa Fernández-Sáiz, Frauke van Bebber, Anne-Kathrin Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop, Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid, Katharina S Götze, Bernhard Kuster, Florian Bassermann
Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins...
July 2016: Nature Medicine
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