BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Demirci, Selami; Zeng, Jing; Wu, Yuxuan; Uchida, Naoya; Shen, Anne H.; Pellin, Danilo; Gamer, Jackson; Yapundich, Morgan; Drysdale, Claire; Bonanno, Jasmine; Bonifacino, Aylin; Krouse, Allen E.; Linde, Nathaniel S.; Engels, Theresa; Donahue, Robert E.; Haro‐Mora, Juan J.; Leonard, Alexis; Nassehi, Tina; Luk, Kevin; Porter, Shaina N.; Lazzarotto, Cícera R.; Tsai, Shengdar Q.; Weiss, Mitchell J.; Pruett-Miller, Shondra M.; Wolfe, Scot A.; Bauer, Daniel E.; Tisdale, John F.

doi:10.1172/jci140189

Cited by 54 publications

(46 citation statements)

References 36 publications

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“…The minor allele frequencies of BCL11A , MYB and HBG2 were all significantly higher in the high HbF group. Primate studies have suggested that erythropoietic stress increases γ-globin gene expression when BCL11A was downregulated using CRISPR-Cas9 editing of its erythroid enhancer [ 43 ].…”

Section: Quantitative Trait Loci Modulating Hbf Productionmentioning

confidence: 99%

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Steinberg

2020

JCM

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Fetal hemoglobin (HbF) usually consists of 4 to 10% of total hemoglobin in adults of African descent with sickle cell anemia. Rarely, their HbF levels reach more than 30%. High HbF levels are sometimes a result of β-globin gene deletions or point mutations in the promoters of the HbF genes. Collectively, the phenotype caused by these mutations is called hereditary persistence of fetal hemoglobin, or HPFH. The pancellularity of HbF associated with these mutations inhibits sickle hemoglobin polymerization in most sickle erythrocytes so that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive complications. Unusually high HbF can also be associated with variants of the major repressors of the HbF genes, BCL11A and MYB. Perhaps most often, we lack an explanation for very high HbF levels in sickle cell anemia.

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Section: Quantitative Trait Loci Modulating Hbf Productionmentioning

confidence: 99%

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Steinberg

2020

JCM

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“…Later studies reported that GATA1 BS-edited cells can efficiently engraft and undergo multilineage differentiation in immunodeficient mice [ 87 , 88 , 89 ]. Safety and efficacy of this approach has also been demonstrated in NHP transplantation experiments, although a decrease in the proportion of edited alleles was observed at the late time points (with frequencies of up to 29%) [ 90 ]. This effective strategy is in an advanced state of clinical development compared to the other genome editing approaches.…”

Section: Nuclease-mediated Strategies For γ-Globin Reactivationmentioning

confidence: 99%

Genome Editing for β-Hemoglobinopathies: Advances and Challenges

Frati

Miccio

2021

JCM

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β-hemoglobinopathies are the most common genetic disorders worldwide and are caused by mutations affecting the production or the structure of adult hemoglobin. Patients affected by these diseases suffer from anemia, impaired oxygen delivery to tissues, and multi-organ damage. In the absence of a compatible donor for allogeneic bone marrow transplantation, the lifelong therapeutic options are symptomatic care, red blood cell transfusions and pharmacological treatments. The last decades of research established lentiviral-mediated gene therapy as an efficacious therapeutic strategy. However, this approach is highly expensive and associated with a variable outcome depending on the effectiveness of the viral vector and the quality of the cell product. In the last years, genome editing emerged as a valuable tool for the development of curative strategies for β-hemoglobinopathies. Moreover, due to the wide range of its applications, genome editing has been extensively used to study regulatory mechanisms underlying globin gene regulation allowing the identification of novel genetic and pharmacological targets. In this work, we review the current advances and challenges of genome editing approaches to β-hemoglobinopathies. Special focus has been directed towards strategies aimed at correcting the defective β-globin gene or at inducing fetal hemoglobin (HbF), which are in an advanced state of clinical development.

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“…Knockout efficiency was confirmed by Western blotting and PCR amplification followed by indel analysis. A guide RNA targeting the AAVS1 "safe harbor" locus was used as a negative control (127). Cell viability was measured at indicated times post-electroporation using the CellTiter-Glo luminescent cell viability assay (Promega G7570).…”

Section: Crispr/cas9 Gene Knockouts By Rnp Electroporationmentioning

confidence: 99%

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

Harada

Heshmati

Kalfon

et al. 2021

Preprint

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A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.

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BCL11A enhancer–edited hematopoietic stem cells persist in rhesus monkeys without toxicity

Cited by 54 publications

References 36 publications

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Genome Editing for β-Hemoglobinopathies: Advances and Challenges

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

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