Emmy Noether Research Group

Project Leader

Profilbild von Priv.-Doz. Dr. med. Jan Krönke

Priv.-Doz. Dr. med. Jan Krönke

Facharzt für Innere Medizin und Hämatologie und Onkologie

Schwerpunkte

Emmy Noether-Nachwuchsgruppenleiter

Contact/Address

Krönke Lab at DRK
AG Krönke/ Internal Medicine III
University Hospital of Ulm
DRK,  Room 1.53
Helmholtzstr. 10
89081 Ulm
Phone +49-(0)731-150-6754

Department of Internal Medicine III
University Hospital of Ulm
Albert-Einstein-Allee 23
89081 Ulm
Germany
Phone: +49-(0)731-500-45718
Fax: +49-(0)731-500-12-45718

Team:

Dr. Stefanie Lindner (Postdoctoral Fellow)
Dr. Stephan Bohl (Clinician Scientist)
Tatjana Meyer (PhD student, IGradU)
Linda Röhner (PhD student, IGradU)
Simon Koepff (Technician)
Denise Miller (Technician)
Dora Nguyen (Master Student)
Hannes Kehm (Master Student)
Imke Bauhuf (Medical Student)
Julian Mauch (Medical Student)
Yannick Buccella (Medical student)

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.

Molecular Mechanism of Lenalidomide

The immunomodulatory drugs (IMID) lenalidomide, thalidomide and pomalidomide are highly active in multiple myeloma and myelodysplastic syndromes (MDS) with deletion of chromosome 5q (del(5q)). We found that all IMiDs act by a previously unrecognized mechanism: Lenalidomide and its analogs modulate the Cereblon (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. Casein Kinase 1a (CK1α) is another lenalidomide-induced CRBN substrate and its depletion induces apoptosis in MDS del(5q) because they are haploinsufficient for CK1α. We further found that non-conserved amino acids in CRBN are responsible for the natural insensitivity of mouse cells to IMiDs.

In our ongoing projects we aim to further understand how lenalidomide and its analogs work in cancer. This includes the establishment of lenalidomide-sensitive mouse models to study their immunomodulatory properties and how they contribute to the anti-cancer effects. In a cooperation with Prof. Dr. Michael Gütschow (Bonn University)  we aim to target other cancer-relevant proteins by chemical modification  of the lenalidomide-structure.

Predictive markers and resistance mechanisms for lenalidomide treatment

While most patients with multiple myeloma respond to lenalidomide, the majority eventually relapses. In cooperation with the Deutsche Studiengruppe Multiples Myelom (DSMM) we are investigating predictive markers and resistance mechanisms with the goal to better guide treatment decisions in patients. For this purpose we apply DNA/RNA Sequencing as well as quantitative proteomics in patient samples obtained before lenalidomide treatment and at relapse. The findings are systematically analyzed by functional genetic analyses with CRISPRS/Cas9  in vitro and in vivo.  

Characterization of 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. Using a combined approach of quantitative proteomics, CRISPR/Cas9-based screens, and  cellular and mouse models we investigate the functional consequences of these mutations and how these aberrant pathways can be targeted.

Grants/Funding

  • Emmy Noether Program (DFG)
  • SFB-1074 (DFG)
  • Else-Kröner Fresenius Stiftung

Selected Publications

Steinebach C, Lindner S, Udeshi ND, Mani DC, Kehm H, Köpff S, Carr SA, Gütschow M, Krönke J. Homo-PROTACs for the Chemical Knockdown of Cereblon. ACS Chem Biol. 2018 Aug 17. doi: 10.1021/acschembio.8b00693. [Epub ahead of print], corresponding authors

Krönke J*, Kuchenbauer F, Kull M, Teleanu V, Bullinger L, Bunjes D, Greiner A, Kolmus S, Köpff S, Schreder M, Mügge LO, Straka C, Engelhardt M, Döhner H, Einsele H, Bassermann F, Bargou R, Knop S, Langer C*: 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). Leukemia. 2017 Jun;31(6):1363-1367 *corresponding authors

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.

Complete list: pubmed

Collaboration Partners

  • Prof. Dr. Florian Bassermann, TU Munich
  • Prof. Dr. Lars Bullinger, Charité Berlin
  • Professor Benjamin L. Ebert, MD/PhD, Brigham and Women’s Hospital, Boston, USA
  • Prof. Dr. Stefan Knop, Prof. Dr. Hermann Einsele, Würzburg University and the German Multiple Myeloma Study Group (DSMM)
  • Prof. Dr. Michael Gütschow, Bonn University
  • Dr. Dirk Heckl,  Hannover Medical School, Hannover, Germany
  • Prof. Dr.Michael Heuser, MD, Hannover Medical School, Hannover, Germany
  • PD Dr. Florian Kuchenbauer, Terry Fox Research Institute, Vancouver
  • Dr. Philipp Mertins, Max-Delbrück Center, Berlin
  • Dr. Namrata Udeshi and Dr. Steven A. Carr, Broad Institute, Cambridge, USA