Targeting transcription factors associated with hemoglobinopathies: Lessons from successful interventions and implications for cancer.

Sickle cell disease and cancer represent fundamentally distinct classes of human disease-one is driven by a defined mutation in β-globin, whereas the other arises through complex genetic and epigenetic alterations that reshape cellular identity and behavior. Despite these differences, both contexts illustrate how transcription factors, chromatin regulators, and cis-regulatory elements can impose disease-relevant gene expression states. In β-hemoglobinopathies, therapeutic reactivation of fetal hemoglobin through modulation of γ-globin (HBG1/2) regulatory pathways, most notably disruption of the erythroid-specific BCL11A enhancer, has emerged as a clinically validated strategy. These advances have been facilitated in part by the HUDEP-2 erythroid progenitor cell line, which provides a tractable adult erythroid model for identifying fetal hemoglobin regulators, validating their function, and evaluating relevant gene editing and gene-regulatory therapies. Many of the regulators implicated in γ-globin silencing, including BCL11A, ZBTB7A, NuRD-associated proteins, DNMT1, KDM1A/LSD1, MYB, and ATF4, also function in cancer-associated transcriptional or epigenetic networks. In cancer, these factors can support oncogenic transcription, tumor suppressor repression, impaired differentiation, stress adaptation, invasion, or therapy resistance. This review summarizes discoveries enabled by HUDEP-2 cells in fetal hemoglobin regulation and hemoglobinopathy therapeutic development, then discusses how these mechanisms provide conceptual parallels for understanding and targeting regulatory dependencies in cancer.