IDH mutations disable the tumor suppressive activity of GSX2 to promote gliomagenesis
Presenter: Yi Xiao, Dr Rer Nat Session: Stem Cell Plasticity and Lineage Reprogramming in Cancer Time: 4/19/2026 2:00:00 PM → 4/19/2026 5:00:00 PM
Authors
Yi Xiao 1 , Diana D. Shi 2 , Lei Guo 1 , Ethan Neumann 1 , Michael M. Levitt 1 , Pranita Kaphle 1 , Tracey Shipman 1 , Haocheng Li 1 , Feng Cai 1 , Denise M. O. Ramirez 1 , Lauren G. Zacharias 1 , Zhenkang Chen 1 , Mathew Lin 2 , Vinesh T. Puliyappadamba 1 , Tao Chen 1 , Milan R. Savani 1 , Salvador Peña 1 , Janaka Wansapura 1 , Thomas P. Mathews 1 , Prashant Mishra 1 , Yoon Jung Kim 1 , Prithvi Raj 1 , Timothy E. Richardson 3 , Jian Xu 4 , Stephen C. Mack 4 , Gilbert J. Rahme 5 , Bradley E. Bernstein 2 , Ralph J. DeBerardinis 1 , Itay Tirosh 6 , Mario L. Suvà 2 , Lin Xu 1 , Kalil G. Abdullah 7 , Samuel K. McBrayer 1 1 UT Southwestern Medical Center, Dallas, TX, 2 Harvard Medical School, Boston, MA, 3 Icahn School of Medicine at Mount Sinai, New York, NY, 4 St. Jude Children’s Research Hospital, Memphis, TN, 5 Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 6 Weizmann Institute of Science, Rehovot, Israel, 7 University of Pittsburgh Medical Center, Pittsburgh, PA
Abstract
Isocitrate dehydrogenase ( IDH ) mutations arise early in glioma development and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. Progress in addressing these questions has been hindered by technical limitations. Patient-derived models rarely capture the biology of tumor initiation, as surgical specimens are obtained only after these phases of cancer evolution have passed. Moreover, the lack of faithful preclinical models of mutant IDH has constrained mechanistic investigation. To overcome these challenges, we developed a genetic mouse model of mutant IDH-driven gliomagenesis and IDH-wildtype companion models to enable direct testing of causal genotype-phenotype relationships involving the Idh1-R132H oncogene. We leveraged these models to survey IDH-mutant glioma initiation by performing time-resolved, joint single-cell RNA and ATAC sequencing analysis of engineered neural cells. Mutant IDH activates neural progenitor cells (NPCs) and drives NPC lineage switching. These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons, a lineage incompatible with mutant IDH-induced transformation. We further find that lineage switching is mediated by promoter hypermethylation and silencing of Gsx2 , a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH while restoring Gsx2 expression in IDH-mutant neurosphere lines impairs their self-renewal and tumorigenic potential. Our work uncovers the molecular mechanisms by which mutant IDH reprograms neural lineage specification to promote cancer initiation, providing a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.
Disclosure
Y. Xiao, None.. D. D. Shi, None.. L. Guo, None.. E. Neumann, None.. M. M. Levitt, None.. P. Kaphle, None.. T. Shipman, None.. H. Li, None.. F. Cai, None.. D. M. O. Ramirez, None.. L. G. Zacharias, None.. Z. Chen, None.. M. Lin, None.. V. T. Puliyappadamba, None.. T. Chen, None.. M. R. Savani, None.. S. Peña, None.. J. Wansapura, None.. T. P. Mathews, None.. P. Mishra, None.. Y. Kim, None.. P. Raj, None. T. E. Richardson, Servier Pharmaceuticals Other, consulting. J. Xu, None.. S. C. Mack, None.. G. J. Rahme, None.. B. E. Bernstein, None. R. J. DeBerardinis, Atavistik Bioscience Other, R.J.D. is a founder and advisor at this company. Vida Ventures Other, R.J.D. is an advisor at this company. Faeth Therapeutics Other, R.J.D. is an advisor at this company. I. Tirosh, None. M. L. Suvà, Immunitas Therapeutics Other, M.L.S. is equity holder, scientific co-founder and advisory board member of Immunitas Therapeutics. L. Xu, None. K. G. Abdullah, Gliomet Other, K.G.A. has intellectual property interests related to brain tumor metabolism and is a co-founder of Gliomet. S. K. McBrayer, Servier Pharmaceuticals ). Gliomet Other, S.K.M. has intellectual property interests related to brain tumor metabolism and is a co-founder of Gliomet.
Cited in
Control: 301 · Presentation Id: 725 · Meeting 21436