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.© 2021 Le Coz et al.
About The Expert
Carole Le Coz
David N Nguyen
Chun Su
Brian E Nolan
Amanda V Albrecht
Suela Xhani
Di Sun
Benjamin Demaree
Piyush Pillarisetti
Caroline Khanna
Francis Wright
Peixin Amy Chen
Samuel Yoon
Amy L Stiegler
Kelly Maurer
James P Garifallou
Amy Rymaszewski
Steven H Kroft
Timothy S Olson
Alix E Seif
Gerald Wertheim
Struan F A Grant
Linda T Vo
Jennifer M Puck
Kathleen E Sullivan
John M Routes
Viktoria Zakharova
Anna Shcherbina
Anna Mukhina
Natasha L Rudy
Anna C E Hurst
T Prescott Atkinson
Titus J Boggon
Hakon Hakonarson
Adam R Abate
Joud Hajjar
Sarah K Nicholas
James R Lupski
James Verbsky
Ivan K Chinn
Michael V Gonzalez
Andrew D Wells
Alex Marson
Gregory M K Poon
Neil Romberg
References
PubMed