Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients PMID: 33951726

ADC Targets in Oncology

2026-04-10

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

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

Carole Le Coz ¹ , David N Nguyen ² ³ ⁴ ⁵ ⁶ , Chun Su ⁷ ⁸ , Brian E Nolan ⁹ ¹⁰ , Amanda V Albrecht ¹¹ , Suela Xhani ¹¹ , Di Sun ¹ , Benjamin Demaree ¹² ¹³ , Piyush Pillarisetti ¹ , Caroline Khanna ¹ , Francis Wright ² ³ , Peixin Amy Chen ³ ⁴ ⁵ ⁶ , Samuel Yoon ¹ , Amy L Stiegler ¹⁴ , Kelly Maurer ¹ , James P Garifallou ¹⁵ , Amy Rymaszewski ¹⁶ , Steven H Kroft ¹⁷ , Timothy S Olson ¹⁸ ¹⁹ , Alix E Seif ¹⁸ ¹⁹ , Gerald Wertheim ²⁰ ²¹ , Struan F A Grant ⁷ ¹⁹ ²² ²³ , Linda T Vo ⁴ ⁵ , Jennifer M Puck ²⁴ ²⁵ ²⁶ , Kathleen E Sullivan ¹ ¹⁹ ²⁷ , John M Routes ¹⁶ , Viktoria Zakharova ²⁸ , Anna Shcherbina ²⁹ , Anna Mukhina ²⁹ , Natasha L Rudy ³⁰ , Anna C E Hurst ³⁰ ³¹ , T Prescott Atkinson ³¹ , Titus J Boggon ¹⁴ ³² , Hakon Hakonarson ¹⁵ ¹⁹ , Adam R Abate ¹² ¹³ ³³ , Joud Hajjar ³⁴ ³⁵ , Sarah K Nicholas ³⁴ ³⁵ , James R Lupski ³⁶ ³⁷ ³⁸ , James Verbsky ¹⁶ , Ivan K Chinn ³⁴ ³⁵ , Michael V Gonzalez ¹⁵ , Andrew D Wells ⁸ ²⁰ ²⁷ , Alex Marson ² ³ ⁴ ⁵ ⁶ ³³ ³⁹ , Gregory M K Poon ¹¹ , Neil Romberg ¹ ¹⁹ ²⁷

Affiliations

1. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.
2. Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.
3. Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.
4. Diabetes Center, University of California San Francisco, San Francisco, CA.
5. Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.
6. Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA.
7. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
8. Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
9. Division of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
10. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.
11. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
12. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.
13. University of California Berkeley-University of California San Francisco Graduate Program in Bioengineering, University of California, San Francisco, CA.
14. Departments of Pharmacology, Yale University, New Haven, CT.
15. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
16. Division of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
17. Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.
18. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
19. Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.
20. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
21. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
22. Division of Diabetes and Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA.
23. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
24. Division of Allergy, Immunology, and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, CA.
25. University of California San Francsico Institute for Human Genetics and Smith Cardiovascular Research Institute, University of California, San Francisco, CA.
26. UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.
27. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
28. Laboratory of Molecular Biology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
29. Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
30. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
31. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
32. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT.
33. Chan Zuckerberg Biohub, San Francisco, CA.
34. William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX.
35. Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX.
36. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
37. Texas Children's Hospital, Houston, TX.
38. Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.
39. Parker Institute for Cancer Immunotherapy, San Francisco, CA.

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.