ArticleThe Journal of experimental medicine2021
Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
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Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed, 71 citations in OpenAlex.
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- A novel SPI1 variant (c.566T > C (p.Ile189Thr)) possibly associated with autosomal dominant agammaglobulinemia in a Chinese girl.BMC pediatrics · 2026Article
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Authors and funding
45 authors at 10 institutions in 2 countries.
Carole Le CozDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-9228-5896
David N NguyenDivision of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.ORCID 0000-0001-6808-2717
Chun SuDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0001-6388-8666
Brian E NolanDivision of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.ORCID 0000-0002-4066-2901
Amanda V AlbrechtDepartment of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.ORCID 0000-0002-7699-0480
Suela XhaniDepartment of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.ORCID 0000-0002-8819-991X
Di SunDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0001-5786-2152
Benjamin DemareeDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.ORCID 0000-0003-2278-6633
Piyush PillarisettiDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0001-6341-0822
Caroline KhannaDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-4356-3933
Francis WrightDivision of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-6471-0648
Peixin Amy ChenDepartment of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-5946-1632
Samuel YoonDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-9151-1660
Amy L StieglerDepartments of Pharmacology, Yale University, New Haven, CT.ORCID 0000-0003-0453-6104
Kelly MaurerDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-2112-8463
James P GarifallouCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-2042-819X
Amy RymaszewskiDivision of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.ORCID 0000-0003-1766-595X
Steven H KroftDepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI.ORCID 0000-0002-4723-6307
Timothy S OlsonDivision of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0003-1288-1960
Alix E SeifDivision of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-1799-2582
Gerald WertheimDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-1585-846X
Struan F A GrantDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0003-2025-5302
Linda T VoDiabetes Center, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-7999-8760
Jennifer M PuckDivision of Allergy, Immunology, and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, CA.ORCID 0000-0001-6623-6276
Kathleen E SullivanDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0003-4018-1646
John M RoutesDivision of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.ORCID 0000-0001-8378-3773
Viktoria ZakharovaLaboratory of Molecular Biology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.ORCID 0000-0001-5949-5317
Anna ShcherbinaDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.ORCID 0000-0002-3113-4939
Anna MukhinaDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.ORCID 0000-0002-3305-1694
Natasha L RudyDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL.ORCID 0000-0003-1314-8461
Anna C E HurstDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL.ORCID 0000-0002-9765-9703
T Prescott AtkinsonDepartment of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.ORCID 0000-0003-2528-6976
Titus J BoggonDepartments of Pharmacology, Yale University, New Haven, CT.ORCID 0000-0003-2862-1637
Hakon HakonarsonCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0003-2814-7461
Adam R AbateDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.ORCID 0000-0001-9614-4831
Joud HajjarWilliam T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX.ORCID 0000-0003-4633-1043
Sarah K NicholasWilliam T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX.ORCID 0000-0003-2163-9607
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.ORCID 0000-0001-9907-9246
James VerbskyDivision of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.ORCID 0000-0001-6682-1002
Ivan K ChinnWilliam T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX.ORCID 0000-0001-5684-5457
Michael V GonzalezCenter for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0001-9741-475X
Andrew D WellsCenter for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-3630-2145
Alex MarsonDivision of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.ORCID 0000-0002-2734-5776
Gregory M K PoonDepartment of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.ORCID 0000-0001-5107-9458
Neil RombergDivision of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.ORCID 0000-0002-1881-5318
Children's Hospital of Philadelphia · USUniversity of California, San Francisco · USBaylor College of Medicine · USMedical College of Wisconsin · USDmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology · RUGeorgia State University · USGladstone Institutes · USUniversity of Alabama at Birmingham · USYale University · USNorthwestern University · US
Funding
Research BaseP30DK063720 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GERMAN, MICHAEL S · 2003 to 2019
$21.8MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MBIOLOGY OF INFECTIOUS DISEASES TRAINING PROGRAMT32AI007641 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MATTHEW G DORSEY · 2000 to 2026
$6.9MT32 Institutional Pediatric ResearchT32HD043021 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI Joseph W. St. Geme · 2002 to 2026
$6.4MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MMUTATIONAL SIGNATURE(S) OF HUMAN GENOMIC REARRANGEMENT MECHANISMSR01GM106373 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI HASTINGS, PHILIP JOHN, LUPSKI, JAMES R. · 2014 to 2022
$3.1MPromoter interactome-aided mapping of unexplored CVID genetic landscapesR01AI146026 · NIAID · CHILDREN'S HOSP OF PHILADELPHIA · PI ROMBERG, NEIL DAVID · 2019 to 2023
$2.9MDirect chemical control of the hematopoietic master transcription factor PU.1R01HL155178 · NHLBI · GEORGIA STATE UNIVERSITY · PI POON, GREGORY MAN KAI · 2021 to 2023
$1.2MCRISPR Editing of Primary Human Cells to Model and Correct Primary Immunodeficiency MutationsK08AI153767 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI NGUYEN, DAVID-HUY NHU · 2020 to 2024
$994kNHGRI NIH HHS UM1 HG006542NHLBI NIH HHS R01 HL155178NIAID NIH HHS K08 AI153767NIAID NIH HHS L40 AI140341NIAID NIH HHS R01 AI146026NICHD NIH HHS T32 HD043021NIDDK NIH HHS P30 DK063720NIGMS NIH HHS R01 GM106373NINDS NIH HHS R35 NS105078
Abstract
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
Indexed as
AdolescentAdultAgammaglobulinemiaB-LymphocytesCell DifferentiationCell LineChildChild, PreschoolChromatinDendritic CellsFemaleGene Expression Regulation, DevelopmentalHEK293 CellsHematopoiesisHematopoietic Stem CellsHumansChromatinProto-Oncogene ProteinsProto-Oncogene Protein Spi-1Trans-Activators
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