title: Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors.
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.
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Brian M
authors.initials: BM
authors.lastname: Dulmovits
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Abena O
authors.initials: AO
authors.lastname: Appiah-Kubi
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Julien
authors.initials: J
authors.lastname: Papoin
authors.affiliation: Red Cell Physiology Laboratory, New York Blood Center, New York, NY;
authors.forename: John
authors.initials: J
authors.lastname: Hale
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Mingzhu
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Sebastien
authors.initials: S
authors.lastname: Didier
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Michael
authors.initials: M
authors.lastname: Gould
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Sehba
authors.initials: S
authors.lastname: Husain-Krautter
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Singh
authors.affiliation: BioTheryX Inc, San Diego, CA;
authors.forename: Kyle W H
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Adrianna
authors.initials: A
authors.lastname: Vlachos
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; North Shore-LIJ Cancer Institute, Lake Success, NY;
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, Unité Mixte de Recherche 5535, Montpellier, France;
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
authors.affiliation: Litwin Zucker Research Center, The Feinstein Institute for Medical Research, Manhasset, NY;
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.affiliation: Red Cell Physiology Laboratory, New York Blood Center, New York, NY;
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
authors.affiliation: Yale Center for Excellence in Molecular Hematology, Yale University School of Medicine, New Haven CT; and.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.affiliation: Red Cell Physiology Laboratory, New York Blood Center, New York, NY;
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.affiliation: 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.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Lipton
authors.affiliation: Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; Les Nelkin Memorial Pediatric Oncology Laboratory, The Feinstein Institute for Medical Research, Manhasset, NY.
authors.forename: Johnson M
authors.initials: JM
authors.lastname: Liu
authors.affiliation: Laboratory of Developmental Erythropoiesis, The Feinstein Institute for Medical Research, Manhasset, NY; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY;
authors.forename: Lionel
authors.identifier: http://orcid.org/0000-0002-0185-6260
authors.initials: L
authors.lastname: Blanc
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics; D002352:Carrier Proteins / Q000097:blood; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000096:biosynthesis; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D056466:Histone Demethylases / Q000097:blood; D006801:Humans; D051740:Ikaros Transcription Factor / Q000097:blood / Q000187:drug effects; D051741:Kruppel-Like Transcription Factors / Q000097:blood; D016086:Lentivirus / Q000235:genetics; D009101:Multiple Myeloma / Q000097:blood / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000097:blood; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins; D055755:SOXD Transcription Factors / Q000097:blood; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D055544:beta-Globins / Q000096:biosynthesis / Q000235:genetics; D055545:gamma-Globins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; C497239:IKZF1 protein, human; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D055544:beta-Globins; C080774:erythroid Kruppel-like factor; D055545:gamma-Globins; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D005319:Fetal Hemoglobin; C467566:pomalidomide; D056466:Histone Demethylases; C495195:KDM1A protein, human; D046988:Proteasome Endopeptidase Complex