GFI1 is a transcriptional repressor essential for hematopoiesis that functions in a cell-context and development-specific manner. It binds to specific DNA sequences in gene promoters and recruits histone deacetylase complexes to suppress genes involved in blood cell development. GFI1 regulates neutrophil differentiation, promotes lymphoid cell proliferation, and is required for granulocyte development. Beyond transcriptional regulation, GFI1 acts as a substrate adapter for PRMT1 in DNA damage responses, facilitating methylation of repair proteins. GFI1 mutations cause autosomal-dominant severe congenital neutropenia, characterized by reduced neutrophil numbers and increased infection risk 1. In acute myeloid leukemia (AML), the germline variant GFI1-36N has a prevalence of 10–15% in AML patients and 5–7% in healthy Caucasians, promoting leukemic development by impairing DNA repair 2. Reduced GFI1 expression accelerates AML progression and predicts inferior prognosis 3. Conversely, upregulated GFI1 expression inhibits leukemic cell growth and induces differentiation, suggesting potential therapeutic benefit 3. Recent evidence identifies GFI1 as a shared regulator of terminal T cell exhaustion and tissue-resident memory T cells, with implications for cancer immunotherapy 4. In AML patients carrying GFI1-36N, combined temozolomide and olaparib therapy shows synthetic lethality, representing a precision medicine approach for this variant.