LonP1 Drives Proneural Mesenchymal Transition in IDH1-R132H Diffuse Glioma

Malignant astroctyoma and glioblastoma are diffuse CNS tumors that have markedly similar features, including microvascular proliferation and necrosis, and the latter presents higher grade and poorer survival. The Isocitrate dehydrogenase 1/2 (IDH) mutation further predicts improved survival and is present in oligodendroglioma and astrocytoma. The latter are more prevalent in younger populations with a median age of 37 years at diagnosis as compared to glioblastoma with a median age of 64(1,2). These tumors frequently have co-occurring ATRX and/or TP53 mutations (Brat et al., 2021). The IDH mutation is known to cause dysregulation of the hypoxia response broadly in CNS tumors and subsequent reduction in both tumor growth and treatment resistance. The frequency of tumor recurrence is high for diffuse CNS tumors. Understanding the mechanism and potential molecular targets enhancing treatment resistance and local invasion in IDH mutant diffuse glioma is necessary for developing new treatment strategies for better tumor control and improving overall survival. Recent evidence highlights the importance of local foci in IDH mutant glioma with an accelerated stress response as responsible for recurrence in these tumors. Here, we demonstrate that LonP1 drives NRF2 and subsequent proneural mesenchymal transition interdependent with the IDH mutation in response to stress and other tumor microenvironment cues. Our findings provide further evidence that targeting LonP1 may be a crucial strategy for improving the standard-of-care treatment in IDH mutant diffuse astrocytoma.