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BCM-UPS SIGNED

Dissecting the role of the ubiquitin proteasome system in the pathogenesis and therapy of B-cell malignancies

Total Cost €

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EC-Contrib. €

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Partnership

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 BCM-UPS project word cloud

Explore the words cloud of the BCM-UPS project. It provides you a very rough idea of what is the project "BCM-UPS" about.

fbxo3    multistep    hypothesis    family    strategy    unravel    interdisciplinary    pathogenesis    mantle    substrates    integrity    biomarkers    aberrant    enzymes    appreciated    cullin    remained    malignancies    therapeutic    pathophysiology    efficacy    disease    mass    models    maintaining    discovered    ubiquitin    roles    oncogenes    genome    candidates    fbxo25    mcl    dub    usp24    critically    imids    candidate    dna    suggests    screens    ubiquitylation    counterparts    genomic    deubiquitylating    events    distinguished    evolution    preclinical    foundation    orphan    multiple    relevance    validate    respectively    global    suppressors    crls    dubs    damage    modalities    fundamental    crbn    machinery    mostly    ligase    drugs    treatment    deregulated    decipher    poor    ring    inhibitors    spectrometry    tumour    myeloma    cohorts    ligases    prognosis    patient    mouse    ups    incurable    proteasome    identities    genetic    cell    crl    instability    lymphoma    serve    imunomodulatory    cellular    reaching    levels    previously    entities    mm    elusive   

Project "BCM-UPS" data sheet

The following table provides information about the project.

Coordinator
KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN 

Organization address
address: ISMANINGER STRASSE 22
city: MUENCHEN
postcode: 81675
website: http://www.med.tu.muenchen.de

contact info
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surname: n.a.
function: n.a.
email: n.a.
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 Coordinator Country Germany [DE]
 Total cost 1˙973˙255 €
 EC max contribution 1˙973˙255 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2015-CoG
 Funding Scheme ERC-COG
 Starting year 2016
 Duration (year-month-day) from 2016-09-01   to  2021-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN DE (MUENCHEN) coordinator 1˙973˙255.00

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 Project objective

B-cell malignancies are characterized by high levels of genomic instability, which critically contribute to their pathogenesis and evolution. Recently, the fundamental role of the ubiquitin proteasome system (UPS) in maintaining genome integrity has been appreciated. Two major new therapeutic modalities in B-cell malignancies, proteasome inhibitors and imunomodulatory drugs (IMiDs), target the UPS and demonstrate particular efficacy in multiple myeloma (MM) and mantle cell lymphoma (MCL), two incurable entities with poor prognosis. This suggests the presence of aberrant ubiquitylation events, whose identities have however remained mostly elusive. Our recent studies identify fundamental roles of orphan ubiquitin ligases of the Cullin Ring ligase family (CRLs) and their counterparts, the deubiquitylating enzymes (DUBs) in the cellular DNA damage response machinery, and characterize these candidates as novel oncogenes or tumour suppressors in MM and MCL. These findings provide the foundation for our hypothesis that deregulated ubiquitylation events involving CRLs and DUBs have a far reaching impact on the pathogenesis of B-cell malignancies and can serve as new therapeutic targets and biomarkers. We therefore propose a multistep strategy in which we will (1) characterize previously orphan CRLs and DUBs, which we have distinguished as candidate oncogenes and tumour suppressors in MM (FBXO3, USP24), MCL (FBXO25), or MM and MCL (CRBN), respectively; (2) decipher the global role of CRLs and DUBs in MM and MCL using defined genetic screens; (3) identify relevant substrates of CRLs/DUBs discovered in (2) using mass spectrometry; and (4) validate CRL/DUB candidates in preclinical mouse models and defined patient cohorts as to their disease relevance. We expect that our interdisciplinary approach will unravel the overall role of the UPS in the pathophysiology, evolution and treatment of B-cell malignancies.

 Publications

year authors and title journal last update
List of publications.
2018 Catharina Wenk, Anne-Kathrin Garz, Sonja Grath, Christina Huberle, Denis Witham, Marie Weickert, Roberto Malinverni, Julia Niggemeyer, Michèle Kyncl, Judith Hecker, Charlotta Pagel, Christopher B. Mulholland, Catharina Müller-Thomas, Heinrich Leonhardt, Florian Bassermann, Robert A. J. Oostendorp, Klaus H. Metzeler, Marcus Buschbeck, Katharina S. Götze
Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis
published pages: 3447-3461, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2018022053
Blood Advances 2/23 2019-06-06

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