Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

J Exp Med. 2021 Jul 5;218(7):e20201750. doi: 10.1084/jem.20201750. Epub 2021 May 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Agammaglobulinemia / genetics*
  • B-Lymphocytes / physiology
  • Cell Differentiation / genetics
  • Cell Line
  • Child
  • Child, Preschool
  • Chromatin / genetics*
  • Dendritic Cells / physiology
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • HEK293 Cells
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Infant
  • Lymphopoiesis / genetics
  • Male
  • Mutation / genetics
  • Precursor Cells, B-Lymphoid / physiology
  • Proto-Oncogene Proteins / genetics*
  • Stem Cells / physiology
  • Trans-Activators / genetics*
  • Young Adult


  • Chromatin
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1