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New epigenetic target and drug in leukemia


Through the investigation of specific interaction partners of the leukemia-associated, truncated variant of C/EBPa, the research group of Giulio Superti-Furga, Scientific Director at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, has gained new mechanistic insights into the molecular details of oncogenic transformation by C/EBPa mutant proteins. Florian Grebien, postdoctoral fellow in Superti-Furga´s team and since 2014 group leader at the Ludwig Boltzmann Institute for Cancer Research, found that the short, leukemic C/EBPa mutant can exert its oncogenic functions through a selective interaction with Wdr5, a critical constituent of histone-methyltransferase complexes that promote gene activation. Genetic inactivation of Wdr5 alleviated the differentiation block in myeloid cells and restored normal maturation in C/EBPa-mutant AML cells. In collaboration with the Structural Genomics Consortium (SGC) Toronto, the researchers at CeMM characterized a novel small molecule that was able to antagonize cellular functions of Wdr5 by disrupting specific protein-protein interactions. This novel chemical compound selectively inhibited the proliferation of AML cells and induced myeloid differentiation in cells from AML patients with N-terminal C/EBPa mutations. Therefore, interfering with Wdr5 represents a new therapeutic strategy for AML with C/EBPa mutations, which warrants attention for clinical development.

10 % of patients with acute myeloid leukemia (AML), a common form of blood cancer in adults, express a shortened form of the transcription factor C/EBPa that lacks a significant portion of the N-terminus of the protein. This short, mutant protein can induce leukemia development by preventing normal myeloid differentiation of blood cells. 


Florian Grebien, Masoud Vedadi, Matthäus Getlik, Roberto Giambruno, Amit Grover, Roberto Avellino, Anna Skucha, Sarah Vittori, Ekaterina Kuznetsova, David Smil, Dalia Barsyte-Lovejoy, Fengling, Gennadiy Poda, Matthieu Schapira, Hong Wu, Aiping Dong, Guillermo Senisterra, Alexey Stukalov, Kilian V M Huber, Andreas Schönegger, Richard Marcellus, Martin Bilban, Christoph Bock, Peter J Brown, Johannes Zuber, Keiryn L Bennett, Rima Al-awar, Ruud Delwel, Claus Nerlov, Cheryl H Arrowsmith and Giulio Superti-Furga. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPa N-terminal leukemia. Nature Chemical Biology, doi:10.1038/nchembio.1859.


CeMM gratefully acknowledges funding from the Austrian Academy of Sciences, the European Research Council and the Austrian Science Fund FWF.