KLF1 is a zinc finger transcription factor essential for erythroid development and a master regulator of globin gene switching 1. During erythropoiesis, KLF1 acts as a dual regulator: it directly activates the adult β-globin gene by binding CACCC box elements in its promoter, while simultaneously activating BCL11A, which represses fetal γ-globin genes, ensuring low fetal hemoglobin levels in adults 2. KLF1 stabilizes occupancy of GATA-1 and TAL1 at the β-globin locus, facilitating active chr19 structure formation 3. Beyond erythropoiesis, KLF1 controls hemoglobin production in chondrocytes under hypoxic conditions through a KLF1-dependent, HIF-independent mechanism 4. Loss-of-function KLF1 mutations cause the Lu(mod) blood group phenotype through heterozygous inactivation 5. Disease-causing mutations in KLF1 produce severe hematologic phenotypes: dominant missense mutations (E325K) cause congenital dyserythropoietic anemia type IV with ultrastructural abnormalities and persistent embryonic/fetal hemoglobin 2, while compound heterozygous loss-of-function mutations cause transfusion-dependent hemolytic anemia 1. Mutant KLF1 exhibits both loss-of-function on wild-type targets and gain-of-function effects activating ectopic genes, with systemic consequences beyond erythroid tissues 6.