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. 

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