Deciphering the effects of IDH mutations on chromatin and differentiation in chondrosarcoma

The discovery of oncogenic neomorphic mutations in the genes coding for the metabolic enzymes Isocitrate Dehydrogenase (IDH) 1 & 2 has driven a search to uncover their oncogenic mechanism and to target them therapeutically. IDH mutations are seen in 50% of chondrosarcomas, which represent approximately 25% of malignant bone neoplasms. The oncogenic proteins they code for result in the inhibition of enzymes normally associated with the removal of repressive chromatin marks. Hence, the outcome of these mutations is usually one of increase heterochromatin content. The consequences of this increased heterochromatin content to tumor development and sensitivity to therapies are not well understood, in particular in the context of solid tumors. Preliminary data presented in this proposal demonstrates that IDH mutations impair the differentiation of untransformed mesenchymal progenitor cells by inhibiting the removal of a repressive chromatin mark (H3K9me2/me3) in genomic regions required for differentiation. This results in an inability to increase the chromatin accessibility of these regions and in the transcriptional repression of the genes within them. Whether this model applies to their oncogenic ability and whether the inhibition of mutant-IDH results in the re-differentiation of tumors harboring these mutations is unknown. This hypothesis will be rigorously tested by 1) using in vitro systems of cancer cell lines harboring endogenous mutations to define the mechanisms by which IDH mutations alter chromatin and impair differentiation; and 2) analyzing pre- and on-treatment samples of locally advanced IDH-mutant chondrosarcoma patients treated with an IDH1-mutant inhibitor to study the consequences of IDH1-mutant inhibition on transcription (RNA-seq), chromatin (ATAC-seq and ChIP-seq) and differentiation. These proposed studies will lead to an enhanced understanding of how metabolic enzyme mutations impair differentiation in chondrosarcomas and unlock the potential of differentiation therapy in solid tumors, a long-sought hurdle of cancer treatment.