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Blood Adv. 2019 May 28;3(10):1586-1597. doi: 10.1182/bloodadvances.2019032318.

The E3 ligase adaptor molecule SPOP regulates fetal hemoglobin levels in adult erythroid cells.

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Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA.
Hematology/Oncology Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA.
Department of Biochemistry and Biophysics and.
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; and.
Genetics Program, The State University of New York at Stony Brook, Stony Brook, NY.


Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and β-thalassemia. To identify new HbF regulators that might be amenable to pharmacologic control, we screened a protein domain-focused CRISPR-Cas9 library targeting chromatin regulators, including BTB domain-containing proteins. Speckle-type POZ protein (SPOP), a substrate adaptor of the CUL3 ubiquitin ligase complex, emerged as a novel HbF repressor. Depletion of SPOP or overexpression of a dominant negative version significantly raised fetal globin messenger RNA and protein levels with minimal detrimental effects on normal erythroid maturation, as determined by transcriptome and proteome analyses. SPOP controls HbF expression independently of the major transcriptional HbF repressors BCL11A and LRF. Finally, pharmacologic HbF inducers cooperate with SPOP depletion during HbF upregulation. Our study implicates SPOP and the CUL3 ubiquitin ligase system in controlling HbF production in human erythroid cells and may offer new therapeutic strategies for the treatment of β-hemoglobinopathies.

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