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

Dulmovits, Brian M.; Appiah‐Kubi, Abena; Papoin, Julien; Hale, John; He, Mingzhu; Al‐Abed, Yousef; Didier, Sébastien; Gould, Michael N.; Husain-Krautter, Sehba; Singh, Sharon; Chan, Kyle; Vlachos, Adrianna; Allen, Sheila; Taylor, Naomi; Marambaud, Philippe; An, Xiuli; Gallagher, Patrick G.; Mohandas, Narla; Lipton, Jeffrey M.; Liu, Johnson M.; Blanc, Lionel

doi:10.1182/blood-2015-09-667923

Cited by 83 publications

(88 citation statements)

References 41 publications

(54 reference statements)

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“…7,15 Identifying regulators of Hb switching including these genetic variants could provide promising predictors of b-thalassemia severity and therapeutic targets for re-activating HbF production. 15,16 The proposed modes of Hb switching based on current discoveries rely on various epigenetic and transcriptional regulatory factors that could have interacting roles in this developmental event. [17][18][19][20] Recently, leukemia/lymphoma-related factor encoded by zinc finger and BTB domain containing 7A (ZBTB7A [MIM 605878]) was identified as a regulator that represents an alternative mechanism independent of the g-globin repressor BCL11A, as it can occupy g-globin genes directly.…”

Section: ]-Hbg2 [Mim 142250]-hbg1 [Mim 142200]-hbd [Mim 142000]mentioning

confidence: 99%

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

Chen

Zuo

Zhang

et al. 2017

The American Journal of Human Genetics

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A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of b-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the b-globin cluster using capture-based next-generation sequencing of 1142 Chinese b-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for b-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of b-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased g-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from b-thalassemia persons. The present study demonstrates that this common rSNP in the proximal A g-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of b-hemoglobinopathy.

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Section: ]-Hbg2 [Mim 142250]-hbg1 [Mim 142200]-hbd [Mim 142000]mentioning

confidence: 99%

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

Chen

Zuo

Zhang

et al. 2017

The American Journal of Human Genetics

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“…Pomalidomide has been recently shown to induce HbF in part by reducing BCL11A transcription (16). We tested the effects of pomalidomide treatment on two HRI-depleted HUDEP2 populations and control HUDEP2 cells.…”

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confidence: 99%

Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells

Grevet

Lan

Hamagami

et al. 2018

Science

129

140

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Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of β-thalassemia.To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase domain–focused CRISPR-Cas9–based genetic screen with a newly optimized single-guide RNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.

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“…Pomalidomide, a drug currently used to treat multiple myeloma, can induce HbF production by reducing the levels of transcriptional repressors of fetal globin gene expression. 11 In addition, Dulmovits et al showed that pomalidomide was effective in inducing HbF expression in erythroid cells from individuals with and without SCD. 11 A Phase I study of pomalidomide in SCD showed promising results, 12 although a phase II study has not been started.…”

Section: Modulating Haemoglobin F and S Expressionmentioning

confidence: 99%

“…11 In addition, Dulmovits et al showed that pomalidomide was effective in inducing HbF expression in erythroid cells from individuals with and without SCD. 11 A Phase I study of pomalidomide in SCD showed promising results, 12 although a phase II study has not been started. Early phase studies of vorinostat and panibostat are either underway or or complete but have yet to report results.…”

Section: Modulating Haemoglobin F and S Expressionmentioning

confidence: 99%

Developing new pharmacotherapeutic approaches to treating sickle‐cell disease

Telen

2016

ISBT Science Series

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Survival for patients with SCD has been prolonged by improvements in supportive care, including vaccinations, antibiotic prophylaxis, and overall medical management, including tra nsfusion. However, there remains only one approved, partially effective drug for sickle cell disease—hydroxyurea (hydroxycarbamide). The world desperately needs better ways of both treating and preventing the recurrent painful vaso-occlusive episodes pathognomonic of sickle cell disease as well as the end-organ damage that still leads inexorably to severely shortened life expectancies throughout the world. Based on accumulating knowledge about how the abnormal red blood cells of sickle cell disease cause the double scourge of acute painful episodes and progressive end-organ damage, both pharmaceutical enterprises and individual investigators are now pursuing multiple new avenues for treating sickle cell disease. As a result, many compounds are in active development, both in preclinical models as well as in phase I, II, and III clinical trials. These agents target many pathophysiologic processes thought to be critical in sickle cell disease, including the chemical and physical behavior of haemoglobin S, cell adhesion, coagulation pathways, platelet activation, inflammatory pathways, and upregulation of haemoglobin F expression. In addition, recent explorations of the genetic variations that predispose to certain types of sickle cell disease-related tissue injury, such as stroke or nephropathy, are expected to lead to identification of drugs targeting the pathways uncovered by such work. Thus, the next five to ten years holds a promise of new treatments for sickle cell disease.

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

Abstract: Key Points Pomalidomide selectively targets BCL11A and SOX6 to induce γ-globin synthesis. The mechanism of action of pomalidomide during erythropoiesis is independent of IKZF1 degradation, in contrast to multiple myeloma.

Cited by 83 publications

References 41 publications

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

A Genetic Variant Ameliorates β-Thalassemia Severity by Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression

Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells

Developing new pharmacotherapeutic approaches to treating sickle‐cell disease

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