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New epigenetic target and drug in leukemia

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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. 

Study:

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.

Funding:

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