Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of gamma-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the BFU-E/CFU-E transition, but without affecting terminal differentiation. Further, the transcription networks involved in gamma-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, since genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide presented increased in vivo gamma-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with beta-hemoglobinopathies.
Faculty; SOM Student; Northwell Researcher
School of Medicine; Northwell Health
General Pediatrics; General Internal Medicine; Hematology/Medical Oncology