Journal
BLOOD
Volume 127, Issue 11, Pages 1481-1492Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-09-667923
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [DK26263]
- National Heart, Lung, and Blood Institute [HL079571]
- New York State Empire Clinical Research Investigator Program award
- Pediatric Cancer Foundation
- Feinstein Institute competitive faculty award
- American Society of Hematology Physician-Scientist Career Development Award
- Allied World St. Baldrick's Scholar Award
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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 burst-forming unit-erythroid/colony-forming unit-erythroid 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, because 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 demonstrated increased in vivo y-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 p-hemoglobinopathies.
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