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  • 1
    Publication Date: 2015-07-02
    Description: Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1alpha degradation. CK1alpha is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1alpha. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kronke, Jan -- Fink, Emma C -- Hollenbach, Paul W -- MacBeth, Kyle J -- Hurst, Slater N -- Udeshi, Namrata D -- Chamberlain, Philip P -- Mani, D R -- Man, Hon Wah -- Gandhi, Anita K -- Svinkina, Tanya -- Schneider, Rebekka K -- McConkey, Marie -- Jaras, Marcus -- Griffiths, Elizabeth -- Wetzler, Meir -- Bullinger, Lars -- Cathers, Brian E -- Carr, Steven A -- Chopra, Rajesh -- Ebert, Benjamin L -- P01 CA066996/CA/NCI NIH HHS/ -- P01CA108631/CA/NCI NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- R01HL082945/HL/NHLBI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):183-8. doi: 10.1038/nature14610. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA [2] University Hospital of Ulm, Department of Internal Medicine III, 89081 Ulm, Germany [3] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Celgene Corporation, San Diego, California 92121, USA. ; Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Roswell Park Cancer Institute, Buffalo, New York 14263, USA. ; University Hospital of Ulm, Department of Internal Medicine III, 89081 Ulm, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Casein Kinase I/genetics/*metabolism ; Cell Line ; Gene Expression Regulation/drug effects ; HEK293 Cells ; Humans ; Immunologic Factors/pharmacology ; Jurkat Cells ; K562 Cells ; Mice ; Molecular Sequence Data ; Myelodysplastic Syndromes/*genetics/*physiopathology ; Peptide Hydrolases/chemistry ; Proteolysis/drug effects ; Sequence Alignment ; Sequence Deletion ; Species Specificity ; Thalidomide/*analogs & derivatives/pharmacology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination/*drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-07-10
    Description: Reproducible workflow for multiplexed deep-scale proteome and phosphoproteome analysis of tumor tissues by liquid chromatography–mass spectrometry Reproducible workflow for multiplexed deep-scale proteome and phosphoproteome analysis of tumor tissues by liquid chromatography–mass spectrometry, Published online: 09 July 2018; doi:10.1038/s41596-018-0006-9 This protocol describes a workflow for multiplexed deep-scale, quantitative proteome and phosphoproteome analysis of tumor tissue samples. The procedure includes step-by-step instructions for all stages, from sample preparation to data analysis.
    Print ISSN: 1754-2189
    Electronic ISSN: 1750-2799
    Topics: Natural Sciences in General
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  • 3
    ISSN: 1573-7462
    Keywords: churn prediction ; neural networks ; decision trees
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract We describe CHAMP (CHurn Analysis, Modeling, andPrediction), an automated system for modeling cellularsubscriber churn that is predicting which customerswill discontinue cellular phone service. We describevarious issues related to developing and deployingthis system including automating data access from aremote data warehouse, preprocessing, featureselection, model validation, and optimization toreflect business tradeoffs. Using data from GTE'sdata warehouse for cellular phone customers, CHAMP iscapable of developing churn models customized byregion for over one hundred GTE cellular phone marketstotaling over 5 million customers. Every month churnfactors are identified for each geographic region andmodels are updated to generate churn scores predictingwho is likely to churn in the short term. Learningmethods such as decision trees and genetic algorithmsare used for feature selection and a cascade neuralnetwork is used for predicting churn scores. Inaddition to producing churn scores, CHAMP alsoproduces qualitative results in the form of rules andcomparison of market trends that are disseminatedthrough a web based interface.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2018-10-05
    Description: Thalidomide and its derivatives, lenalidomide and pomalidomide, are clinically effective treatments for multiple myeloma and myelodysplastic syndrome with del(5q). These molecules lack activity in murine models, limiting investigation of their therapeutic activity or toxicity in vivo. Here, we report the development of a mouse model that is sensitive to thalidomide derivatives because of a single amino acid change in the direct target of thalidomide derivatives, cereblon (Crbn). In human cells, thalidomide and its analogs bind CRBN and recruit protein targets to the CRL4 CRBN E3 ubiquitin ligase, resulting in their ubiquitination and subsequent degradation by the proteasome. We show that mice with a single I391V amino acid change in Crbn exhibit thalidomide-induced degradation of drug targets previously identified in human cells, including Ikaros (Ikzf1), Aiolos (Ikzf3), Zfp91, and casein kinase 1a1 (Ck1α), both in vitro and in vivo. We use the Crbn I391V model to demonstrate that the in vivo therapeutic activity of lenalidomide in del(5q) myelodysplastic syndrome can be explained by heterozygous expression of Ck1α in del(5q) cells. We found that lenalidomide acts on hematopoietic stem cells with heterozygous expression of Ck1α and inactivation of Trp53 causes lenalidomide resistance. We further demonstrate that Crbn I391V is sufficient to confer thalidomide-induced fetal loss in mice, capturing a major toxicity of this class of drugs. Further study of the Crbn I391V model will provide valuable insights into the in vivo efficacy and toxicity of this class of drugs.
    Keywords: Myeloid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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