Title

Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors

Publication Date

January 2015

Journal Title

Blood

Abstract

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.

Document Type

Article

EPub Date

2015/12/19

Facility

School of Medicine

Primary Department

Molecular Medicine

Additional Departments

Pediatrics; Medicine

PMID

26679864

DOI

10.1182/blood-2015-09-667923

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