2026/05/26 by Mariam Hakobyan, Jens Langstein, Maria Jose Ramos Medina +25 · 2 voices
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #Acute Myeloid Leukemia Research #Blood disorders and treatments #Immune cells in cancer
paper · doi:10.1182/blood.2025031268
openalex publication_date 2026/05/26 · openalex created_date 2026/05/28 · openalex updated_date 2026/07/22
IDH1 and IDH2 are frequently mutated in various cancers, including acute leukemias. However, the distinct mechanisms by which mutant IDH1 or IDH2 drive hematopoietic neoplasms remain poorly understood. Here, we analyzed DNA methylation in IDH1- and IDH2-mutant AML and found neutrophil lineage-specific epigenetic alterations in IDH1-mutant cases that went along with severely impaired neutrophil differentiation. Transcriptional analysis of normal hematopoiesis in humans and mice revealed a strong physiological upregulation of IDH1/Idh1 in myeloid progenitors. To study the functional effects of Idh1 mutations on hematopoiesis in a pre-leukemic setting, we used a genetically engineered inducible mouse model expressing a heterozygous Idh1 mutation under control of the endogenous promotor. Our study revealed a cell-intrinsic block in neutrophil differentiation caused by repression of myeloid transcription programs in neutrophil progenitors. This included impaired expression of Cebpe, which encodes a key transcription factor regulating neutrophil differentiation. Reactivation of Cebpe expression, by overexpression of its upstream regulator Cebpa or following treatment with hypomethylating agents restored differentiation, indicating that the differentiation block is reversible.In summary, we found a reversible, pre-leukemic impairment of neutrophil differentiation in IDH1-mutant hematopoiesis that correlates with elevated IDH1 expression in myeloid progenitors and likely explains the strong association of IDH1 mutations with myeloid neoplasms.