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

Lan, Xianjiang; Khandros, Eugene; Huang, Peng; Peslak, Scott A.; Bhardwaj, Saurabh K.; Grevet, Jeremy D.; Abdulmalik, Osheiza; Wang, Hongxin; Keller, Cheryl A.; Giardine, Belinda; Baeza, Josue; Duffner, Emily R.; Demerdash, Osama E.; Wu, Xiaoli; Vakoc, Christopher R.; García, Benjamin A.; Hardison, R; Shi, Junwei; Blobel, Gerd A.

doi:10.1182/bloodadvances.2019032318

Cited by 27 publications

(15 citation statements)

References 31 publications

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“…The domainfocused CRISPR single guide RNA (sgRNA) library was constructed, and CRISPR screen of HbF enrichment was performed as previously described. 9,14…”

Section: Transcription Factor Crispr Screenmentioning

confidence: 99%

The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression

Huang

Peslak

Lan

et al. 2020

Blood

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Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9–guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.

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“…The domainfocused CRISPR single guide RNA (sgRNA) library was constructed, and CRISPR screen of HbF enrichment was performed as previously described. 9,14…”

Section: Transcription Factor Crispr Screenmentioning

confidence: 99%

The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression

Huang

Peslak

Lan

et al. 2020

Blood

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“…SPOP overexpression accelerated AML cell proliferation and suppressed apoptosis. SPOP has been acknowledged as a substrate adaptor of the CUL3 ubiquitin ligase complex, which functions as a potential inhibitor of fetal hemoglobin [27]. The oncogenic function of SPOP has been identified in prior studies.…”

Section: Discussionmentioning

confidence: 99%

SPOP accelerates acute myeloid leukemia initiation and development through miR-183-mediated METAP2 inhibition

Sun

et al. 2020

Preprint

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Background: Recent miRNA profiling studies have implicated the potential use of miRNAs as as diagnostic and prognostic indicators in acute myeloid leukemia (AML), which has been reportedly implicated in the interplay with certain mRNAs. Herein this study, we intend to characterize the functional relevance of SPOP/miR-183/METAP2 axis in AML in vivo and in vitro. Methods: Differentially expressed mRNAs and downstream regulatory miRNA were predicted by in silico analysis. We induced SPOP/miR-183/METAP2 overexpression or inhibition to examine their effects on AML cell proliferation and apoptosis in vitro and tumor growth in vivo , along with their interaction with β-catenin. Results: SPOP and miR-183 were highly expressed, while METAP2 was poorly expressed in patient peripheral blood samples and cell lines of AML. SPOP accelerated the proliferation of AML cells and repressed apoptosis. Mechanistically, SPOP enhanced β-catenin protein stability and nuclear translocation leading to upregulated expression of miR-183. MiR-183 facilitated proliferation and inhibited apoptosis of AML cells by targeting METAP2. Furthermore, miR-183 inhibition and METAP2 overexpression reversed SPOP-induced AML cell malignancy. Besides, in vitro findings were reproduced by in vivo findings. Conclusion: SPOP stimulated AML malignant progression by inducing β-catenin stability and miR-183/METAP2 axis activation, highlighting a potential therapeutic target against AML recurrence and metastasis.

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“…The understanding of the switch from γ‐globin to β‐globin production during infancy, and the control of this switch by various transcription factors (TF) has provided new targets for gene‐modifications. Kruppel like factor (KLF1), Speckle‐type POZ protein (SPOP), leukemia/lymphoma related factor (LRF) and B‐cell leukemia/lymphoma 11a (BCL11a) are now recognized to be important TFs, that bind to specific sites in the HBB gene and control the switch from production of HbF to HbA 18‐20 . Although it is traditionally considered that TF regulate the rate at which the linked promoter transcribes mRNA, it is also postulated that TF instead act to increase the probability that a linked unit will establish and maintain transcriptional activity 21 …”

Section: Methodsmentioning

confidence: 99%

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

Soni

2020

American J Hematol

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Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of β‐globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene editing strategies now allow for efficient ex‐vivo genetic manipulation of human stem cells that can lead to production of hemoglobin, leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene‐therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase clinical trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β‐thalassemia.

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

Cited by 27 publications

References 31 publications

The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression

The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression

SPOP accelerates acute myeloid leukemia initiation and development through miR-183-mediated METAP2 inhibition

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

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