ArticleCell stem cell2021
Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.
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Article in Cell stem cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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35citing papers in PubMed, 1 pooled it
6.4field-weighted citation impact, top 3% of its field
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Clinical relevance of SCN and CyN induced by ELANE mutations: a systematic review.Frontiers in immunology · 2024Pooled it
- Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice.Nature biomedical engineering · 2026Article
- Engineered dCas12f1-SAM enables robust transcriptional activation and gain-of-function screening in primary human cells.Nature communications · 2026Article
- ELANE inhibits the progression of osteosarcoma via suppressing the CXCL12/CXCR4 axis.Molecular and cellular biochemistry · 2026Article
- Article
- Targeted inhibition ofMolecular therapy. Methods & clinical development · 2025Article
- CRISPR-based therapeutic genome editing for inherited blood disorders.Nature reviews. Drug discovery · 2025Review
- Dissecting cellular ecosystem with single-cell CRISPR screens.Blood science (Baltimore, Md.) · 2025Article
- Mechanism of sepsis regulation by ELANE via macrophage polarization.Scientific reports · 2025Article
- HAX1 inhibits apoptosis and promotes maturation of neutrophils.Cell communication and signaling : CCS · 2025Article
- Review
- Precision engineering of human cytomegalovirus without BAC constraints: a Sendai virus-delivered CRISPR/Cas9 approach.The Journal of general virology · 2025Article
- Flavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Article
- Machine learning-based prediction reveals kinase MAP4K4 regulates neutrophil differentiation through phosphorylating apoptosis-related proteins.PLoS computational biology · 2025Article
- Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.Cell stem cell · 2025Article
- Case Report: Heterozygous out-of-frame frameshift variant inFrontiers in immunology · 2025Article
- G-CSF resistance of ELANE-mutant neutropenia depends on SERF1-containing truncated-neutrophil elastase aggregates.The Journal of clinical investigation · 2024Article
- Comparison of Gene-Editing Approaches for Severe Congenital Neutropenia-Causing Mutations in theThe CRISPR journal · 2024Article
- SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution.Cell genomics · 2024Article
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Authors and funding
24 authors at 5 institutions in 2 countries.
Shuquan RaoDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Yao YaoDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Josias Soares de BritoDepartments of Pediatrics and of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Qiuming YaoDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02129, USA.
Anne H ShenDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Ruth E WatkinsonDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Alyssa L KennedyDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Steven CoyneDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Chunyan RenDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Jing ZengDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Anna Victoria SerbinDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard College, Cambridge, MA 02138, USA.
Sabine StuderDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Kaitlyn BallottiDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Chad E HarrisDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Kevin LukDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Christian S StevensDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Myriam ArmantDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Luca PinelloMolecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02129, USA.
Scot A WolfeDepartment of Molecular, Cell and Cancer Biology, Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Roberto ChiarleDepartment of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Akiko ShimamuraDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Benhur LeeDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Peter E NewburgerDepartments of Pediatrics and of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Daniel E BauerDivision of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Broad Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bauer@bloodgroup.tch.harvard.edu.
Broad Institute · USUniversity of Massachusetts Chan Medical School · USIcahn School of Medicine at Mount Sinai · USBoston Children's Hospital · USHarvard University · US
Funding
Severe Chronic Neutropenia International RegistryR24AI049393 · NIAID · UNIVERSITY OF WASHINGTON · PI DALE, DAVID CHANDLER · 2004 to 2019
$10.6MSystems Biology of Bone Marrow Failure and MDS for Precision MedicineRC2DK122533 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI FIGUEROA, MARIA EUGENIA, FLEMING, MARK D · 2019 to 2023
$6.4MPathobiology of VPS45 severe congenital neutropeniaR01AI152446 · NIAID · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI MUNSON, MARY, NEWBURGER, PETER E · 2020 to 2024
$3.5MGene editing ELANE to understand and treat severe congenital neutropeniaR01HL150553 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI BAUER, DANIEL EVAN, NEWBURGER, PETER E · 2020 to 2023
$3.0MSequence analysis of hemotological traits in African AmericansR01HL130733 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LANGE, ETHAN MATHER, REINER, ALEXANDER P · 2016 to 2019
$2.7MMultiscale exploration of the functional non-coding genomeR35HG010717 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI PINELLO, LUCA · 2019 to 2023
$2.6MNHGRI NIH HHS R35 HG010717NHLBI NIH HHS R01 HL130733NHLBI NIH HHS R01 HL150553NIAID NIH HHS R01 AI152446NIAID NIH HHS R24 AI049393NIDDK NIH HHS RC2 DK122533
Abstract
Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing of early exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function. Conversely, terminal exon frameshift alleles that mimic SCN-associated mutations escaped NMD, recapitulated neutrophil maturation arrest, and established an animal model of ELANE-mutant SCN. Surprisingly, only -1 frame insertions or deletions (indels) impeded neutrophil maturation, whereas -2 frame late exon indels repressed translation and supported neutrophil maturation. Gene editing of primary HSPCs allowed faithful identification of variant pathogenicity to clarify molecular mechanisms of disease and encourage a universal therapeutic approach to ELANE-mutant neutropenia, returning normal neutrophil production and preserving HSPC function.
Indexed as
Leukocyte ElastaseNeutropeniaAnimalsCongenital Bone Marrow Failure SyndromesGene EditingHumansMutationVirulenceLeukocyte ElastaseCRISPR screenELANEframeshifthematopoietic stem and progenitor cellsnonsense-mediated decaysevere congenital neutropeniatherapeutic gene editingtranslational repressionunfolded protein responsexenograft mouse model
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