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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.
Röhner, L., Ng, Y.L.D.,… Krönke, J. Generation of a lenalidomide-sensitive syngeneic murine in vivo multiple myeloma model by expression of CrbnI391V. Exp Hematol. 2021; 93:61-69.e4.
Steinebach C, Ng D,…, Krönke J. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chemical Science. 2020; 11(13): 3474-3486
Meyer T, Jahn N, Lindner S,…, Krönke J. Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1). Leukemia. 2020 Feb;34(2):404-415.
Steinebach C, Lindner S, Udeshi ND,…, Krönke J†. Homo-PROTACs for the Chemical Knockdown of Cereblon. ACS Chem Biol. 2018;13(9):2771-82.
Krönke J*, Fink E*, Hollenbach P,…, 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, …, 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, ..., Döhner K. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122(1):100-8.
Krönke J, Schlenk RF, Jensen KO,…, 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
- Wilhelm Sander-Stiftung
- Berliner Krebsgesellschaft
- German Cancer Consortium (DKTK)
- Emmy Noether Programm - DFG
- Sonderforschungsbereich 1074 - DFG