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

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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}

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 -