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Emmy Noether Research Group

Contact/Address

Principle Investigator:

Dr. Jan Krönke

Department of Internal Medicine III

University Hospital of Ulm

Albert-Einstein-Allee 23

89081 Ulm

Germany

Phone:

Phone (Lab):

FAX:

jan.kroenke[at]uni-ulm.de

0049-731-500-45718

0049-731-150-6786

0049-731-500-45525

Lab Members:

Stefanie Lindner (Postdoc)

Simon Koepff (BTA)

Tatjana Meyer (PhD student)

Linda Röhner (PhD student)

Dilan Serdar (PhD student)

Yannick Buccella (MD student)

stefanie.lindner[at]uni-ulm.de

simon.koepff[at]uniklinik-ulm.de

tatjana.meyer[at]posteo.de

linda.roehner[at]uni-ulm.de

dilan.serdar[at]uni-ulm.de

yannick.buccella[at]uni-ulm.de

Research Fields

Our group is interested in the role of ubiquitin ligases and other members of the ubiquitin-proteasome pathway in the pathogenesis of cancer and how these enzymes can be exploited as drug targets.

 

A) Molecular Mechanism of Lenalidomide

The immunomodulatory drugs (IMID) lenalidomide, thalidomide and pomalidomide are highly active in multiple myeloma and other B cell lymphomas. We recently found that these drugs modulate the CRBN-DDB1-CUL4A-ROC1 (CRBN-CRL4) E3 ubiquitin ligase to specifically ubiquitinate the lymphoid transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos), resulting in their proteasomal degradation (Krönke et al., Science 2014). Depletion of IKZF1 and IKZF3 selectively inhibits growth of multiple myeloma cells and increases IL2 release in T cells, explaining two major properties of lenalidomide.

Our current aim is to identify additional CRBN substrates that are implicated in other effects of lenalidomide like its clinical activity in myelodysplastic syndrome (MDS) with del(5q) using quantitative proteomics, biochemical studies, and mouse models. 

B) Predictive markers and resistance mechanisms for lenalidomide treatment

The ability to predict response of a certain treatment is essential for personalized medicine. Based on the molecular mechanism of lenalidomide and its analogues we are aiming to identify markers that predict sensitivity and resistance to these drugs in patients treated with these compounds. For this purpose we are applying Next Generation Sequencing-based approaches in patient samples obtained before lenalidomide treatment and at relapse. Findings from these analyses are further functionally investigated in cell lines. 

C) Mutations in the ubiquitin-proteasome pathway in hematologic malignancies

Recent large-scale sequencing analyses of cancer genomes identified recurrent mutations in several genes involved in the ubiquitin-proteasome pathway including ubiquitin ligases and de-ubiquitinating enzymes. For most of these mutations the exact mechanism how they lead to malignant transformation is unknown. Using a combined approach of proteomics, molecular biology, cellular and mouse models we aim to investigate the functional consequences of these mutations and how these aberrant pathways can be targeted.

Representative publications

 

Krönke J*, Fink EC*, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND,  Chamberlain PP, Mani DR, Man HW, Gandhi AK, Svinkina T, Schneider RK, McConkey M, Järås M, Griffiths E, Wetzler M, Bullinger L, Cathers BE, Carr SA, Chopra R, Ebert BL. Lenalidomide induces ubiquitination and degradation of casein kinase 1A1 in del(5q) MDS. Nature. 2015 Jul 9;523(7559):183-8. *contributed equally 

Krönke J, Udeshi N, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL. Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells. Science. 2014 Jan 17;343(6168):301-5.

Krönke J, Bullinger L, Teleanu V, Tschürtz F, Gaidzik VI, Kühn MW, Rücker FG, Holzmann K, Paschka P, Kapp-Schwoerer S, Späth D, Kindler T, Schittenhelm M, Krauter J, Ganser A, Göhring G, Schlegelberger B, Schlenk RF, Döhner H, Döhner K. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013 Jul 4;122(1):100-8.

Krönke J, Schlenk RF, Jensen KO, Tschürtz F, Corbacioglu A, Gaidzik VI, Paschka P, Onken S, Eiwen K, Habdank M, Späth D, Lübbert M, Wattad M, Kindler T, Salih HR, Held G, Nachbaur D, von Lilienfeld-Toal M, Germing U, Haase D, Mergenthaler HG, Krauter J, Ganser A, Göhring G, Schlegelberger B, Döhner H, Döhner K. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011 Jul 1;29(19):2709-16.

Bullinger L*, Krönke J*, Schön C*, Radtke I, Urlbauer K, Botzenhardt U, Gaidzik V, Carió A, Senger C, Schlenk RF, Downing JR, Holzmann K, Döhner K, Döhner H. Identification of Acquired Copy Number Alterations and Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia Using High-Resolution Single Nucleotide Polymorphism Analysis. Leukemia 2010; 24: 438-49  *equal contribution

Complete list: pubmed

Funding/ Grants

  • Emmy Noether Program (Deutsche Forschungsgemeinschaft)
  • Start-up funding by the SFB-1074 (Deutsche Forschungsgemeinschaft)
  • Else-Kröner Fresenius Stiftung

External Collaborations

  • Benjamin L. Ebert, MD/PhD, Brigham and Women’s Hospital, Boston, USA
  • Steven A. Carr, PhD, Broad Institute, Cambridge, USA
  • Dirk Heckl, PhD, Hannover Medical School, Hannover, Germany
  • Michael Heuser, MD, Hannover Medical School, Hannover, Germany
  • German Multiple Myeloma Study Group (DSMM)

Forschungsbereiche

Molecular Genetics of Myeloid Leukemia
Prof. Dr. Konstanze Döhner / Prof. Dr. Lars Bullinger

Molecular Genetics of Myeloproliferative Disorders
Dr. Frank Stegelmann / Prof. Dr. Konstanze Döhner

Molecular Pathogenesis and Progression of Lymphoproliferative Disorders
Prof. Dr. Stephan Stilgenbauer

Mechanisms of Leukemogenesis
PD Dr. Daniel Mertens

Molecular Pathogenesis and Prognostic Markers in Monoclonal Gammopathies
PD Dr. Christian Langer

Tumor Immunology Group (TIG)
Prof. Dr. Jochen Greiner

Haemostaseology
PD Dr. Christian Langer
 

Molecular Hematopoiesis
PD Dr. Dr. Florian Kuchenbauer

 

Emmy Noether Research Group

Dr. Jan Krönke

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