One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them

One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them Publisher Pubmed

Knox AVC¹ ; Cominsky LY^{1, 2} ; Sun D¹ ; Cruz Cabrera E¹ ; Nolan BE^{3, 4} ; Ofray E¹ ; Benetti E^{5, 6} ; Visconti C^{7, 8} ; Barzaghi F^{6, 8} ; Rosenzweig SD⁹ ; Lawrence MG¹⁰ ; Sullivan KE^{1, 11, 12} ; Yoon S¹ ; Rachimi S^{1, 2} Show All Authors

Knox AVC¹
Cominsky LY^{1, 2}
Sun D¹
Cruz Cabrera E¹
Nolan BE^{3, 4}
Ofray E¹
Benetti E^{5, 6}
Visconti C^{7, 8}
Barzaghi F^{6, 8}
Rosenzweig SD⁹
Lawrence MG¹⁰
Sullivan KE^{1, 11, 12}
Yoon S¹
Rachimi S^{1, 2}
Padem N¹³
Conboy E¹⁴
Stojanovic M^{15, 16}
Petrovic G¹⁷
Pasic S^{16, 17}
Church J^{18, 19}
Ferdman RM^{18, 19}
Candotti F²⁰
Arlabosse T²¹
Theodoropoulou K²¹
Dutmer CM²²
Marodi L²³
Szucs G²⁴
Broides A²⁵
Nahum A²⁵
Levy J²⁵
Kettunen K²⁶
Daddali R²⁷
Seppanen M^{27, 28}
Vanttinen M^{29, 30}
Martelius T³¹
Gronholm J^{27, 32}
Peri M^{33, 34}
Azzari C^{33, 34}
Ricci S^{33, 34}
Ojaimi S^{35, 36}
Edwards ESJ³⁷
Van Zelm MC^{37, 38}
Sun J³⁹
Abolhassani H^{40, 41}
Panhammarstrom Q⁴⁰
Hakonarson H^{11, 42, 43}
Mayr D^{44, 45}
Boztug K^{46, 47}
Boisson B⁴⁸
Casanova JL^{48, 49, 50}
Le Coz C⁵¹
Poon GMK⁵²
Romberg N^{1, 11, 12}

Show Affiliations

1. Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA, United States
2. Immunology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
3. Division of Rheumatology, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States
4. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
5. Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
6. San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
7. Vita-Salute San Raffaele University, Milan, Italy
8. Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy
9. Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, United States
10. Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA, United States
11. Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, United States
12. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
13. Division of Pediatric Pulmonology, Allergy-Immunology, and Sleep Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
14. Department of Medical and Molecular Genetics, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
15. Clinic of Allergy and Immunology, University Clinical Center of Serbia, Belgrade, Serbia
16. Department of Medicine, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
17. Department of Immunology, Mother and Child Health Care Institute of Serbia, Belgrade, Serbia
18. Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, CA, United States
19. Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
20. Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
21. Department of Woman, Mother, Child, Unit of Pediatric Immunology, Allergology and Rheumatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
22. Department of Pediatrics, Section of Allergy and Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
23. Department of Dermatology, Primary Immunodeficiency Clinical Unit and Laboratory, Semmelweis University, Budapest, Hungary
24. Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
25. Pediatric Immunology Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
26. Laboratory of Genetics, HUS Diagnostic Center, University of Helsinki, Helsinki, Finland
27. Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
28. Rare Diseases Center and Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
29. Department of Medicine, Unit of Infectious Diseases and Hospital Hygiene, Kuopio University Hospital, Kuopio, Finland
30. Wellbeing Services, County of North Savo, Kuopio, Finland
31. Inflammation Center, Department of Infectious Disease, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland
32. Division of Hematology, Oncology, and Stem Cell Transplantation and Pediatric Research Center, New Children's Hospital, HUS Helsinki University Hospital, Helsinki, Finland
33. Department of Health Sciences, University of Florence, Florence, Italy
34. Meyer Children's Hospital IRCCS, Florence, Italy
35. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia
36. Monash Health Pathology, Monash Health, Clayton, VIC, Australia
37. Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia
38. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands
39. Department of Clinical Immunology, Children's Hospital of Fudan University, National Children Medical Center, Shanghai, China
40. Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
41. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
42. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
43. Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
44. Saint Anna Children's Cancer Research Institute, Vienna, Austria
45. Department of Dermatology, Medical University of Vienna, Vienna, Austria
46. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
47. Center for Molecular Medicine Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
48. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
49. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France
50. Howard Hughes Medical Institute, New York, NY, United States
51. Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, National Centre for Scientific Research, INSERM, Toulouse, France
52. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, United States

Source: Blood Published:2025

Abstract

Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B-cell and dendritic-cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency was recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss-of-function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of individuals harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and noninfectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic-cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks. © 2025

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Style	Citing Format
MLA	Knox AVC, et al.. "One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them." Blood, vol. 145, no. 22, 2025, pp. 2549-2560.
APA	Knox AVC, Cominsky LY, Sun D, Cruz Cabrera E, Nolan BE, Ofray E, Benetti E, Visconti C, Barzaghi F, Rosenzweig SD, Lawrence MG, Sullivan KE, Yoon S, Rachimi S, Padem N, Conboy E, Stojanovic M, Petrovic G, Pasic S, ... Romberg N (2025). One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them. Blood, 145(22), 2549-2560.
Chicago	Knox AVC, Cominsky LY, Sun D, Cruz Cabrera E, Nolan BE, Ofray E, Benetti E, et al.. "One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them." Blood 145, no. 22 (2025): 2549-2560.
Harvard	Knox AVC et al. (2025) 'One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them', Blood, 145(22), pp. 2549-2560.
Vancouver	Knox AVC, Cominsky LY, Sun D, Cruz Cabrera E, Nolan BE, Ofray E, et al.. One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them. Blood. 2025;145(22):2549-2560.
BibTex	@article{ author = {Knox AVC and Cominsky LY and Sun D and Cruz Cabrera E and Nolan BE and Ofray E and Benetti E and Visconti C and Barzaghi F and Rosenzweig SD and Lawrence MG and Sullivan KE and Yoon S and Rachimi S and Padem N and Conboy E and Stojanovic M and Petrovic G and Pasic S and Church J and Ferdman RM and Candotti F and Arlabosse T and Theodoropoulou K and Dutmer CM and Marodi L and Szucs G and Broides A and Nahum A and Levy J and Kettunen K and Daddali R and Seppanen M and Vanttinen M and Martelius T and Gronholm J and Peri M and Azzari C and Ricci S and Ojaimi S and Edwards ESJ and Van Zelm MC and Sun J and Abolhassani H and Panhammarstrom Q and Hakonarson H and Mayr D and Boztug K and Boisson B and Casanova JL and Le Coz C and Poon GMK and Romberg N}, title = {One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them}, journal = {Blood}, volume = {145}, number = {22}, pages = {2549-2560}, year = {2025} }
RIS	TY - JOUR AU - Knox AVC AU - Cominsky LY AU - Sun D AU - Cruz Cabrera E AU - Nolan BE AU - Ofray E AU - Benetti E AU - Visconti C AU - Barzaghi F AU - Rosenzweig SD AU - Lawrence MG AU - Sullivan KE AU - Yoon S AU - Rachimi S AU - Padem N AU - Conboy E AU - Stojanovic M AU - Petrovic G AU - Pasic S AU - Church J AU - Ferdman RM AU - Candotti F AU - Arlabosse T AU - Theodoropoulou K AU - Dutmer CM AU - Marodi L AU - Szucs G AU - Broides A AU - Nahum A AU - Levy J AU - Kettunen K AU - Daddali R AU - Seppanen M AU - Vanttinen M AU - Martelius T AU - Gronholm J AU - Peri M AU - Azzari C AU - Ricci S AU - Ojaimi S AU - Edwards ESJ AU - Van Zelm MC AU - Sun J AU - Abolhassani H AU - Panhammarstrom Q AU - Hakonarson H AU - Mayr D AU - Boztug K AU - Boisson B AU - Casanova JL AU - Le Coz C AU - Poon GMK AU - Romberg N TI - One Hundred Thirty-Four Germ Line Pu.1 Variants and the Agammaglobulinemic Patients Carrying Them JO - Blood VL - 145 IS - 22 SP - 2549 EP - 2560 PY - 2025 ER -

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