Project Details

Role of HIF-1α signaling in Ollier disease and Maffucci syndrome

Daiana Drehmer, PhD

Summary

BACKGROUND: Ollier disease (OD) and Maffucci syndrome (MS) are rare genetic conditions characterized by the presence of multiple enchondromas, and MS patients also develop vascular anomalies. Symptoms appear at an early age including pain, limb deformities and pathological fractures, and around 50% of patients develop cancer. GAP: Somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants are found in around 80% of patients with OD-MS. Previous work by our group found novel germline variants in the hypoxia-inducible factor (HIF) pathway in around 22% of OD-MS patients (Poll et al., 2022). HIF-1α plays an essential role in cellular adaptation to hypoxia in physiology and disease, and the effect of HIF-1α activity in OD-MS is unknown. HYPOTHESIS: Impaired HIF-1α signaling contributes to the OD-MS phenotype. METHODS: We will engineer by CRISPR selected novel HIF-1α variants identified in the patients with OD and MS. We will analyze the impact of HIF-1α variants as well as IDH1 WT or mutant p.R132H on HIF transcriptional activity, protein levels, and expression of HIF target genes. We will evaluate the impact of IDH1 inhibitor Ivosidenib as well as HIF inhibitors in vitro in cells harboring IDH1 and HIF-1α variants. RESULTS: Pending. IMPACT: There is no established treatment for OD-MS, and further insights into the role of IDH and HIF variants in OD-MS will inform whether using IDH1 inhibitors or HIF inhibitors may benefit patients.