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Blood. 2016 Mar 17;127(11):1481-92. doi: 10.1182/blood-2015-09-667923. Epub 2015 Dec 17.

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

Author information

1
Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
2
Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY;
3
Red Cell Physiology Laboratory, New York Blood Center, New York, NY;
4
Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY;
5
Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
6
BioTheryX Inc, San Diego, CA;
7
Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; North Shore-LIJ Cancer Institute, Lake Success, NY;
8
Institut de Génétique Moléculaire de Montpellier, Unité Mixte de Recherche 5535, Montpellier, France;
9
Litwin Zucker Research Center, The Feinstein Institute for Medical Research, Manhasset, NY;
10
Yale Center for Excellence in Molecular Hematology, Yale University School of Medicine, New Haven CT; and.
11
Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; Les Nelkin Memorial Pediatric Oncology Laboratory, The Feinstein Institute for Medical Research, Manhasset, NY.
12
Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; Les Nelkin Memorial Pediatric Oncology Laboratory, The Feinstein Institute for Medical Research, Manhasset, NY.

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 γ-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 γ-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 γ-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 β-hemoglobinopathies.

PMID:
26679864
PMCID:
PMC4797024
DOI:
10.1182/blood-2015-09-667923
[Indexed for MEDLINE]
Free PMC Article

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