IDH1 R132

These results suggest an association of PRDM16 overexpression with the NPM1/FLT3-ITD/DNMT3A triple-mutant AML genotype, typically linked to high leukemia stem cell frequencies and poor prognosis. Importantly, within this adverse AML subtype low PRDM16 expression is an independent prognostic marker for favorable outcome, supporting an anti-leukemic mechanism in AMLs with repressed PRDM16 transcription.

Disrupting KMT2A-mediated H3K4me3 reshapes the epigenome and attenuates LGG-relevant programs and phenotypes in vitro, supporting a strong role in tumor initiation. In vivo, the TS603 survival result highlights context-dependent maintenance and motivates cautious, microenvironment-aware therapeutic exploration of the KMT2A axis and downstream targets such as SCD.

P1, N=30, Not yet recruiting, Servier Bio-Innovation LLC | Initiation date: Sep 2025 --> Jan 2026

Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.

P2, N=103, Recruiting, Alpheus Medical, Inc. | Not yet recruiting --> Recruiting

Mechanistically, the dual IDH1/ATRX alteration upregulates pro-ferroptotic genes (HMOX1 and ACSL4) while downregulating anti-ferroptotic genes (SLC7A11 and GPX4), thereby sensitizing GBM cells to ferroptosis induction. Together, our findings provide new biological insights into IDH1/ATRX-driven GBM pathogenesis and highlight ferroptosis as a potential therapeutic vulnerability in this aggressive tumor subtype.

P3, N=57, Active, not recruiting, Servier | Recruiting --> Active, not recruiting | Trial completion date: Jun 2031 --> Oct 2030 | Trial primary completion date: Jun 2026 --> Oct 2025

P1, N=21, Completed, Istituto Oncologico Veneto IRCCS | Active, not recruiting --> Completed | N=36 --> 21

P2, N=28, Recruiting, University of California, Davis | Not yet recruiting --> Recruiting

This study expands the genetic and morphologic repertoire of TCCRP with implications and pitfalls for accurate diagnosis. The findings highlight the IDH1/IDH2 dichotomy with convergence of phenotype in these rare breast tumours.

Overall, the results were highly satisfactory, particularly regarding MRD assessment, and highlighted key points for improvement, especially in baseline detection of FLT3-TKD2 and IDH1 mutations. This study represents the first collaborative initiative to evaluate performance of AML molecular targets within a laboratory network and underscores the importance of regular exercises to monitor performance, identify and resolve technical or interpretive discrepancies to ultimately ensure accurate clinical decision-making.

While the mechanism of action of these compounds as IDH inhibitors is yet to be established, our results support these compounds as potent and selective hits. They offer a promising foundation for structural optimisation and the development of next-generation therapeutics against MT-IDH1 malignancies.