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Krönke Group

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Focus of research

Ubiquitin-proteasome pathway in the pathogenesis of cancer

The ubiquitin-proteasome-system is an essential cellular pathway that regulates stability and function of proteins. In cancer cells ubiquitination is frequently deregulated by mutation or aberrant expression of ubiquitin ligases and deubiquitinating enzymes. Moreover, recently we and others found that drugs like thalidomide analogs hijack ubiquitin ligases to rapidly degrade cancer-related proteins including those that were previously considered undruggable such as transcription factors. The focus of our research is to determine the impact of deregulated protein ubiquitination and protein stability in hematologic malignancies. We apply comprehensive proteomic and genetic analyses in primary patient samples combined with CRISPR/Cas9 functional genetics to uncover disease driving and resistance mediating alterations in the ubiquitin-proteasome system. In addition, we study new compounds like proteolysis-targeting chimeras (PROTACs) that direct ubiquitin ligases to proteins as targeted treatments for cancer. The ultimate goal is to translate our findings into the clinic for personalized treatments.

 

Group Leader

Prof. Dr. med. Jan Krönke

W2-Professor für Pathogenese hämatopoetischer Neoplasien

CBF: Campus Benjamin Franklin

Selected publications

  • Meyer T, Jahn N, Lindner S, Röhner L, Dolnik A, Weber D, Scheffold A, Köpff S, Paschka P, Gaidzik VI, Heckl D, Wiese S, Ebert BL, Döhner H, Bullinger L, Döhner K, Krönke J. Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1). Leukemia. 2019 Oct 1.
  • Cocciardi S, Dolnik A, Kapp-Schwoerer S, Rücker FG, Lux S, Blätte TJ, Skambraks S, Krönke J, Heidel FH, Schnöder TM, Corbacioglu A, Gaidzik VI, Paschka P, Teleanu V, Göhring G, Thol F, Heuser M, Ganser A, Weber D, Sträng E, Kestler HA, Döhner H, Bullinger L*, Döhner K*. Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation. Nature Commun. 2019;10(1):2031. *Equal contribution.
  • Steinebach C, Kehm H, Lindner S, Vu LP, Köpff S, López Mármol Á, Weiler C, Wagner KG, Reichenzeller M, Krönke J†, Gütschow M†. PROTAC-mediated crosstalk between E3 ligases. Chem Commun. 2019;55(12):1821-24.
  • 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;13(9):2771-82.
  • 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;31(6):1363-67. *Equal contribution
  • Krönke J*, Fink E*, Hollenbach P, MacBeth K, Hurst S, Udeshi N, Chamberlain P, Mani D, Man H, Gandhi A, Svinkina T, Schneider R, McConkey M, Järås M, Griffiths E, Wetzler M, Bullinger L, Cathers B, Carr S, Chopra R, Ebert B. Lenalidomide induces ubiquitination and degradation of casein kinase 1A1 in del(5q) MDS. Nature. 2015;523(7559):183-8. *Equal contribution.
  • Krönke J, Udeshi ND, 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;343(6168):301-5.
  • Krönke J, Bullinger L, Teleanu V, Tschürtz F, Gaidzik VI, Kühn MW, Rücker FG, Holzmann K, Paschka P, Kapp-Schwörer 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;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;29(19):2709-16.

Funding sources

  • Emmy Noether Programm - DFG
  • Sonderforschungsbereich 1074 - DFG
  • Wilhelm Sander-Stiftung