T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In a recently published work, we identified and characterized a tumor suppressor role for the Polycomb Repressive Complex 2 (PRC2), that was underlined through the identification of loss-of-function mutations and deletions of members of the PRC2 complex in 25% of the patients with T cell leukemia. Further inhibition of PRC2 action in T cell leukemia comes through competition with master oncogenes, such as Notch1, for chromatin binding. Extending our work on the H3K27me3 mark, we now show that the activity of the corresponding H3K27me3 demethylases is also very important for the initiation, progression and maintenance of the disease. More specifically, transcriptional data analysis and exome sequencing of primary T-ALL samples demonstrates a significant correlation between levels and mutational status of these demethylases and major oncogenic pathways in leukemia. Functionally, genomic ablation of these epigenetic modulators as well as targeting with a specific-recently produced and characterized-inhibitor-GSKJ4, leads to apoptosis and cell cycle arrest of T-ALL lines in vitro and in vivo, accompanied by major epigenetic and transcriptional changes at specific anti-apoptotic, oncogenic and metabolic genes. Furthermore, genetic ablation of these epigenetic modulators leads to slower initiation of the disease in a classic mouse model of leukemia with highly improved survival rates. In light of recent developments of novel epigenetic inhibitors against these molecules, these findings pave the way to specific pharmacological targeting of T cell leukemia.
Citation Format: Panagiotis Ntziachristos, Aris Tsirigos, Thomas Trimarchi, Evangelia Loizou, Xu Luyao, Pieter Van Vlierberghe, Bryan King, Grant Welstead, Charles Mullighan, Rudolf Jaenisch, Adolfo Ferrando, Iannis Aifantis. Characterizing the specific oncogenic and tumor suppressor roles of H3K27me3 epigenetic modulators in T cell leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A07.