Analysis of mutant IDH, TP53 and ATRX mediated interactions in IDH mutant Astrocytoma

• Applicants: Professor Dr. Andreas von Deimling; Privatdozent Dr. Stefan Pusch
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 498037705

Isocitrate dehydrogenase (IDH)-mutant Astrocytoma are among the most common primary human brain tumors. Besides mutations in the IDH1 or IDH2 gene, the majority of these tumors also harbor mutations in the genes TP53 and ATRX. Due to this coincidence we hypothesize that mutations in these genes are mandatory for the development of IDH-mutant Astrocytoma. The effects of TP53 mutations have been intensely investigated. In contrast the role of IDH mutations in Astrocytoma is much less understood and the role of ATRX has not been analyzed in detail so far. Most of the current knowledge on IDH-mutant Astrocytoma was acquired from native human tumor specimens. However, analysis of interaction of coinciding mutations in tumor development requires suitable model systems. Such models must allow for modulation and analysis each mutation separately. The combinations and the timing of the occurrence of mutations should be variable. In addition, the activation of the events should be possible at different stages of differentiation. A model combining IDH, TP53 and ATRX and fulfilling the conditions formodulation does not exist. We intend analyzing the effects of these three mutations occurring upon single or combined occurrence. By using differentiation specific promoters, we will gain new insight towards the cell of origin of astrocytoma. For this purpose, we will use our novel conditional recombinant mouse model which just now hasbeen generated in our lab. We will primarily rely on extensive proteomic analysis by mass spectrometry and additional cell biological analysis. With this project we aim for the first systematic analysis of these three co-occurring mutations in IDH-mutant Astrocytoma. We expect to gain fundamental and novel insights on the mechanism that drive these tumors.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. David E. Reuß